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nlmixr

This is an example of a complex model that can be estimated.

In the example below, a target-mediated drug disposition PK model for nimotuzumab is illustrated (Rodríguez-Vera et al. 2015).

Model Schematic

nlmixr model


library(nlmixr2)
library(xpose)
library(xpose.nlmixr2)
library(ggplot2)

nimo <- function() {
  ini({
    ## Note that the UI can take expressions
    ## Also note that these initial estimates should be provided on the log-scale
    tcl <- log(0.001)
    tv1 <- log(1.45)
    tQ <- log(0.004)
    tv2 <- log(44)
    tkss <- log(12)
    tkint <- log(0.3)
    tksyn <- log(1)
    tkdeg <- log(7)
    ## Initial estimates should be high for SAEM ETAs
    eta.cl  ~ 2
    eta.v1  ~ 2
    eta.kss ~ 2
    ##  Also true for additive error (also ignored in SAEM)
    add.err <- 10
  })
  model({
    cl <- exp(tcl + eta.cl)
    v1 <- exp(tv1 + eta.v1)
    Q  <- exp(tQ)
    v2 <- exp(tv2)
    kss <- exp(tkss + eta.kss)
    kint <- exp(tkint)
    ksyn <- exp(tksyn)
    kdeg <- exp(tkdeg)

    k <- cl/v1
    k12 <- Q/v1
    k21 <- Q/v2

    eff(0) <- ksyn/kdeg ##initializing compartment

    ## Concentration is calculated
    conc = 0.5*(central/v1-eff-kss)+0.5*sqrt((central/v1-eff-kss)**2+4*kss*central/v1)

    d/dt(central)  = -(k+k12)*conc*v1+k21*peripheral-kint*eff*conc*v1/(kss+conc)
    d/dt(peripheral) = k12*conc*v1-k21*peripheral  ##Free Drug second compartment amount
    d/dt(eff) = ksyn - kdeg*eff - (kint-kdeg)*conc*eff/(kss+conc)

    IPRED=log(conc)

    IPRED ~ add(add.err)
  })
}

Fit

fit <- nlmixr(nimo, nimoData, est="saem")
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> [====|====|====|====|====|====|====|====|====|====] 0:00:00 
#> 
#> 001: -7.082156   0.240380    -5.322648   3.706002    2.535890    -1.294407   -0.102901   1.975165    1.900000    1.900000    2.150501    1.391724    
#> 002: -7.318608   0.337788    -5.472643   3.604174    2.671940    -1.381532   0.004361    1.965802    1.805000    1.805000    2.042976    0.830852    
#> 003: -7.004796   0.329353    -5.552719   3.663648    2.576095    -1.342266   0.094213    2.169032    1.714750    1.714750    1.940827    0.704378    
#> 004: -6.831052   0.337039    -5.509392   3.581316    2.619975    -1.473308   0.193564    2.039580    1.629012    1.629012    1.843786    0.673922    
#> 005: -6.988888   0.327350    -5.438457   3.546217    2.611964    -1.375401   0.032029    2.028963    1.547562    1.547562    1.751597    0.664592    
#> 006: -6.877438   0.309723    -5.508254   3.692787    2.673534    -1.385796   -0.048632   1.984854    1.470184    1.470184    1.664017    0.659652    
#> 007: -6.898159   0.314886    -5.496362   3.638982    2.747608    -1.255406   -0.026410   1.947620    1.407505    1.396675    1.580816    0.663774    
#> 008: -6.957871   0.319272    -5.352725   3.503540    2.776519    -1.197933   0.000427    1.968390    1.337130    1.326841    1.501775    0.670739    
#> 009: -6.826759   0.315714    -5.227308   3.580258    2.922322    -1.203666   -0.010643   2.177228    1.270273    1.260499    1.483524    0.661929    
#> 010: -7.082397   0.308379    -5.273932   3.611745    2.874421    -1.137025   0.115752    2.203563    1.305004    1.197474    1.517557    0.656455    
#> 011: -7.083805   0.294951    -5.267117   3.697103    2.937389    -1.228824   0.136825    2.298366    1.239753    1.137600    1.522041    0.661686    
#> 012: -7.229129   0.369998    -5.290768   3.737127    2.879780    -1.195137   0.181972    2.281019    1.177766    1.080720    1.445939    0.660513    
#> 013: -7.118783   0.316777    -5.198435   3.808386    3.007388    -1.298448   0.173969    2.200194    1.118877    1.026684    1.545758    0.659895    
#> 014: -7.107046   0.296195    -5.247466   3.826552    3.068812    -1.449512   0.198110    2.171824    1.062934    0.975350    1.468470    0.664804    
#> 015: -7.101186   0.342107    -5.262732   3.789245    3.006193    -1.467174   0.209708    2.105610    1.173838    0.926582    1.395047    0.661338    
#> 016: -7.054116   0.293809    -5.404022   3.710325    2.800496    -1.446669   0.248707    2.016275    1.115146    0.880253    1.325294    0.661297    
#> 017: -6.900522   0.299893    -5.468624   3.730384    2.913575    -1.388838   0.287952    2.001241    1.059389    0.836241    1.259030    0.662951    
#> 018: -6.847400   0.259424    -5.462242   3.782073    2.941709    -1.430433   0.325918    2.151714    1.006419    0.794429    1.196078    0.674475    
#> 019: -6.753272   0.299121    -5.510133   3.743449    2.954801    -1.441600   0.390829    2.220912    0.956098    0.754707    1.136274    0.665982    
#> 020: -6.837756   0.315087    -5.621735   3.778400    2.916021    -1.288673   0.366226    2.244962    1.106701    0.716972    1.079461    0.667779    
#> 021: -6.893220   0.306474    -5.591735   3.473458    2.872476    -1.289627   0.381579    2.338688    1.255998    0.681123    1.025488    0.670320    
#> 022: -7.005703   0.363949    -5.581785   3.500052    2.745047    -1.268654   0.294263    2.201461    1.193198    0.647067    0.974213    0.668004    
#> 023: -6.939491   0.324638    -5.455178   3.494135    2.667590    -1.310115   0.298623    2.255601    1.133538    0.614714    0.925503    0.653433    
#> 024: -6.885500   0.269202    -5.425549   3.477327    2.519646    -1.295313   0.341746    2.453918    1.201937    0.583978    0.879227    0.657180    
#> 025: -7.003679   0.329172    -5.462586   3.450449    2.399445    -1.392637   0.407089    2.493273    1.141840    0.554779    0.835266    0.657478    
#> 026: -6.998503   0.308081    -5.503414   3.378182    2.240570    -1.395307   0.507344    2.538508    1.084748    0.527040    0.793503    0.652995    
#> 027: -6.983049   0.251959    -5.415440   3.357185    2.331519    -1.429724   0.469920    2.487613    1.053474    0.500688    0.753828    0.653142    
#> 028: -7.064152   0.281134    -5.428507   3.340922    2.360536    -1.343881   0.489512    2.441413    1.031793    0.475654    0.744672    0.656158    
#> 029: -7.153328   0.259568    -5.408880   3.332953    2.419550    -1.396986   0.552957    2.412138    1.038802    0.451871    0.755118    0.654489    
#> 030: -7.137799   0.269775    -5.430981   3.324828    2.505459    -1.450748   0.544276    2.356400    0.986862    0.429278    0.717362    0.654892    
#> 031: -7.278104   0.306992    -5.462212   3.347481    2.481115    -1.393738   0.510631    2.404250    0.937519    0.407814    0.681494    0.653134    
#> 032: -7.366002   0.296299    -5.462750   3.354325    2.493465    -1.385500   0.511527    2.445562    0.890643    0.387423    0.647419    0.659970    
#> 033: -7.126602   0.319700    -5.438877   3.445812    2.471803    -1.441491   0.498690    2.510886    0.846111    0.368052    0.615049    0.662377    
#> 034: -7.011533   0.319809    -5.457466   3.448620    2.549336    -1.433274   0.440205    2.477871    0.803806    0.349649    0.601210    0.661287    
#> 035: -7.030069   0.328177    -5.430406   3.521252    2.568902    -1.477423   0.431840    2.497634    0.777766    0.332167    0.571150    0.669576    
#> 036: -6.790538   0.306774    -5.527834   3.622364    2.476747    -1.425994   0.382638    2.494380    0.738878    0.315558    0.542592    0.668018    
#> 037: -6.800334   0.270544    -5.414146   3.402385    2.582889    -1.400895   0.474395    2.576823    0.818234    0.299781    0.560308    0.659367    
#> 038: -6.779983   0.198230    -5.460225   3.326120    2.459665    -1.312269   0.425136    2.498573    0.777322    0.284791    0.532293    0.662861    
#> 039: -6.671886   0.254019    -5.570037   3.257240    2.441459    -1.403449   0.505908    2.453239    0.738456    0.270552    0.552395    0.655443    
#> 040: -6.801421   0.264928    -5.582054   3.187304    2.426505    -1.432948   0.510497    2.418150    0.701533    0.257024    0.524775    0.661263    
#> 041: -6.867235   0.280701    -5.643455   3.254848    2.508290    -1.478873   0.516456    2.354902    0.719071    0.258599    0.498537    0.658930    
#> 042: -6.780870   0.297515    -5.625829   3.229796    2.525800    -1.423885   0.545876    2.247574    0.704235    0.262364    0.473610    0.656337    
#> 043: -7.000980   0.308498    -5.643916   3.368084    2.518038    -1.448837   0.571972    2.253661    0.838864    0.261131    0.449929    0.660254    
#> 044: -6.881316   0.361812    -5.676801   3.302498    2.485286    -1.378273   0.610588    2.406006    0.796921    0.287254    0.427433    0.659041    
#> 045: -6.992270   0.311070    -5.460939   3.297823    2.493164    -1.394428   0.574134    2.346399    0.987389    0.272891    0.406061    0.657335    
#> 046: -6.937286   0.255586    -5.505305   3.189254    2.469744    -1.477122   0.595653    2.387849    0.938020    0.259247    0.385758    0.657275    
#> 047: -6.910055   0.278884    -5.524470   3.291595    2.395307    -1.531927   0.560231    2.426453    0.891119    0.261829    0.366470    0.657160    
#> 048: -7.067394   0.288722    -5.510406   3.356396    2.365454    -1.578588   0.642720    2.429590    0.846563    0.296891    0.348147    0.655746    
#> 049: -6.923328   0.270119    -5.450789   3.414379    2.366448    -1.585423   0.629513    2.466967    0.893002    0.282046    0.330739    0.658189    
#> 050: -6.975794   0.288132    -5.435516   3.347858    2.392924    -1.608769   0.643707    2.417948    0.932213    0.277081    0.314202    0.648781    
#> 051: -6.875901   0.353712    -5.416865   3.611819    2.462963    -1.660868   0.661059    2.438330    0.970314    0.294981    0.298492    0.652593    
#> 052: -6.765307   0.271983    -5.391472   3.626409    2.527210    -1.643741   0.684367    2.440789    0.921799    0.288411    0.283568    0.655201    
#> 053: -6.620037   0.310457    -5.451163   3.854368    2.628403    -1.630681   0.646037    2.405277    0.875709    0.273990    0.269389    0.661798    
#> 054: -6.541914   0.322377    -5.602161   3.918050    2.661677    -1.588618   0.619825    2.408575    0.831923    0.260291    0.255920    0.656715    
#> 055: -6.373490   0.295359    -5.581440   3.790033    2.702007    -1.567283   0.614160    2.346308    0.843537    0.265659    0.284322    0.657369    
#> 056: -6.361577   0.312322    -5.637698   3.785505    2.787302    -1.527121   0.574659    2.272041    0.801360    0.252376    0.270106    0.659265    
#> 057: -6.297834   0.286892    -5.705691   3.762464    2.794607    -1.540606   0.548523    2.251223    0.761292    0.239758    0.276525    0.662021    
#> 058: -6.402065   0.258021    -5.810660   3.777895    2.758826    -1.493502   0.544410    2.192527    0.862540    0.263461    0.262699    0.656945    
#> 059: -6.488559   0.275667    -5.779645   3.824903    2.822481    -1.496432   0.516002    2.169180    0.941809    0.280023    0.249564    0.661064    
#> 060: -6.537952   0.322100    -5.844695   4.198486    2.774870    -1.501122   0.532435    2.161901    0.894719    0.287462    0.237086    0.663263    
#> 061: -6.416021   0.343720    -5.758680   3.940205    2.650611    -1.499860   0.520846    2.224032    0.849983    0.273089    0.225231    0.664169    
#> 062: -6.310170   0.299830    -5.611265   3.839088    2.686540    -1.439855   0.487623    2.288302    0.807484    0.259434    0.213970    0.663122    
#> 063: -6.294908   0.311997    -5.540899   3.862490    2.707261    -1.423113   0.494748    2.327657    0.767109    0.246462    0.203271    0.660175    
#> 064: -6.366629   0.316682    -5.694336   3.936071    2.652013    -1.427522   0.492013    2.282279    0.835532    0.234139    0.193108    0.670102    
#> 065: -6.180801   0.364973    -5.741631   3.493918    2.689585    -1.489510   0.476151    2.215031    0.793756    0.235573    0.183452    0.667527    
#> 066: -6.179648   0.348374    -5.749013   3.402021    2.762067    -1.490865   0.520905    2.185092    0.929906    0.254211    0.174280    0.661183    
#> 067: -6.263086   0.327637    -5.634331   3.234640    2.755069    -1.510695   0.550426    2.217312    0.979119    0.322320    0.176250    0.662333    
#> 068: -6.292892   0.362669    -5.612425   3.180375    2.701803    -1.509967   0.559493    2.262292    0.930163    0.306204    0.209163    0.659376    
#> 069: -6.406907   0.311112    -5.588864   2.947345    2.659620    -1.506976   0.586969    2.254385    1.083297    0.321730    0.198705    0.665014    
#> 070: -6.314687   0.246440    -5.595287   2.908022    2.630289    -1.497341   0.549582    2.261500    1.029132    0.314350    0.206450    0.657920    
#> 071: -6.217709   0.265446    -5.567675   2.798543    2.600281    -1.531825   0.566408    2.206204    0.977676    0.298633    0.196128    0.659110    
#> 072: -6.157095   0.238023    -5.754847   2.756068    2.610835    -1.545311   0.590166    2.188482    0.928792    0.302674    0.215475    0.656766    
#> 073: -6.287617   0.255763    -5.782974   2.668018    2.562220    -1.547860   0.620664    2.168260    0.961688    0.313501    0.204701    0.659373    
#> 074: -6.509203   0.260687    -5.652472   2.846293    2.500960    -1.562527   0.515292    2.121736    1.267267    0.297826    0.194466    0.668704    
#> 075: -6.416412   0.278495    -5.663658   2.889233    2.531158    -1.575245   0.563700    2.156104    1.203903    0.282935    0.184743    0.660703    
#> 076: -6.372197   0.258099    -5.726064   2.809855    2.497007    -1.585770   0.554655    2.130951    1.143708    0.268788    0.175506    0.656914    
#> 077: -6.345672   0.278881    -5.670182   2.647593    2.595867    -1.575106   0.604909    2.152797    1.189868    0.296868    0.166730    0.657233    
#> 078: -6.348930   0.262330    -5.658917   2.462042    2.552281    -1.543080   0.649866    2.176722    1.130374    0.282025    0.158394    0.658202    
#> 079: -6.182329   0.305910    -5.622486   2.681155    2.576799    -1.530473   0.609340    2.235116    1.073856    0.267924    0.151881    0.666624    
#> 080: -6.278351   0.247696    -5.611191   2.640099    2.540012    -1.529954   0.613512    2.216091    1.020163    0.254528    0.152491    0.665660    
#> 081: -6.161229   0.308140    -5.648894   2.746375    2.584527    -1.542349   0.612081    2.185029    0.969155    0.251895    0.144867    0.658389    
#> 082: -6.134250   0.290519    -5.697368   2.861817    2.573103    -1.554697   0.594581    2.126595    0.920697    0.239300    0.137623    0.654481    
#> 083: -6.157780   0.293400    -5.674551   2.596083    2.552749    -1.554927   0.613874    2.102997    0.874662    0.227335    0.130742    0.649084    
#> 084: -6.043718   0.270041    -5.524905   2.548757    2.544325    -1.547110   0.572517    2.204878    0.830929    0.215968    0.132570    0.649058    
#> 085: -6.035218   0.203893    -5.464928   2.517038    2.519986    -1.562535   0.583354    2.289152    0.809167    0.205170    0.125942    0.659515    
#> 086: -6.155169   0.188440    -5.358699   2.760529    2.498737    -1.578073   0.580119    2.283462    0.904021    0.194911    0.120566    0.652513    
#> 087: -6.115400   0.156386    -5.284803   2.778030    2.502999    -1.590966   0.603655    2.235995    0.858820    0.185166    0.114538    0.654176    
#> 088: -6.158905   0.168182    -5.450443   2.449863    2.516668    -1.578885   0.565575    2.174054    0.887651    0.235742    0.113189    0.672454    
#> 089: -6.264660   0.164214    -5.592644   2.405672    2.533449    -1.562987   0.581745    2.165362    1.141834    0.228379    0.107530    0.663633    
#> 090: -6.279971   0.227163    -5.563073   2.419175    2.545061    -1.556209   0.595420    2.181293    1.239181    0.235747    0.102153    0.659207    
#> 091: -6.211909   0.182332    -5.561700   2.445815    2.572867    -1.544233   0.596836    2.182525    1.177222    0.223959    0.128134    0.653343    
#> 092: -6.054699   0.227844    -5.661706   2.325238    2.516278    -1.536466   0.568745    2.156513    1.118361    0.212761    0.122333    0.654642    
#> 093: -6.060565   0.272713    -5.729856   2.462729    2.511964    -1.535758   0.574684    2.156639    1.062443    0.212576    0.116217    0.657862    
#> 094: -6.246009   0.287082    -5.862449   2.551871    2.478441    -1.539652   0.606569    2.199354    1.234343    0.247500    0.110406    0.654755    
#> 095: -6.430293   0.274664    -5.696054   2.580877    2.460005    -1.534625   0.608098    2.271460    1.691609    0.236875    0.104886    0.658308    
#> 096: -6.235785   0.261008    -5.573622   2.627211    2.484236    -1.537258   0.653057    2.253702    1.607029    0.225031    0.099641    0.659037    
#> 097: -6.424872   0.273861    -5.622372   2.356470    2.528754    -1.536887   0.689467    2.268328    1.556114    0.213780    0.094659    0.654865    
#> 098: -6.292736   0.285177    -5.715682   2.226018    2.579253    -1.531399   0.684539    2.272246    1.600298    0.203091    0.089926    0.662134    
#> 099: -6.272271   0.291946    -5.757178   2.435993    2.512930    -1.534143   0.677665    2.285231    1.520283    0.224477    0.095242    0.661522    
#> 100: -6.212044   0.249385    -5.898241   2.320787    2.509986    -1.546925   0.700892    2.320300    1.444269    0.213253    0.123807    0.664829    
#> 101: -6.145608   0.204983    -5.761245   2.475931    2.517424    -1.559297   0.720140    2.349080    1.372055    0.202590    0.117616    0.663993    
#> 102: -6.088134   0.202131    -5.798948   2.318193    2.482019    -1.557104   0.714314    2.330478    1.303453    0.192461    0.111736    0.656278    
#> 103: -6.155875   0.197593    -5.842397   2.162408    2.429311    -1.566786   0.730617    2.305273    1.238280    0.182838    0.106149    0.656881    
#> 104: -6.087011   0.207827    -5.953135   2.118611    2.511587    -1.562439   0.767974    2.280894    1.176366    0.188620    0.100841    0.666994    
#> 105: -6.039989   0.251439    -5.966304   2.123777    2.549131    -1.557299   0.757149    2.254959    1.117548    0.253200    0.095799    0.666102    
#> 106: -6.290345   0.268955    -5.975043   2.145418    2.573836    -1.550764   0.743828    2.239197    1.151869    0.245265    0.091009    0.659745    
#> 107: -6.286730   0.287510    -5.955899   2.111745    2.594305    -1.561735   0.747215    2.250038    1.094275    0.248733    0.086459    0.659499    
#> 108: -6.273823   0.297585    -6.016208   2.113022    2.595285    -1.566934   0.734420    2.258948    1.039562    0.277755    0.082136    0.660153    
#> 109: -6.267443   0.316282    -6.038765   2.197108    2.609124    -1.577313   0.734572    2.255037    1.005796    0.315716    0.078029    0.661130    
#> 110: -6.157332   0.269255    -6.051623   2.140537    2.550621    -1.569779   0.731601    2.273520    0.955506    0.299930    0.074935    0.659734    
#> 111: -6.076713   0.269728    -5.953031   2.187567    2.523093    -1.573527   0.738749    2.270180    0.907731    0.284934    0.078932    0.655210    
#> 112: -5.964195   0.169871    -5.815473   2.113463    2.501764    -1.570052   0.722121    2.274298    0.931897    0.270687    0.079653    0.658917    
#> 113: -6.037903   0.193654    -5.686140   2.183916    2.521836    -1.569770   0.686944    2.272125    0.885302    0.257152    0.075670    0.656216    
#> 114: -6.212603   0.207454    -5.578621   2.227185    2.468546    -1.572799   0.704449    2.289144    0.852730    0.244295    0.071886    0.659052    
#> 115: -6.087506   0.159465    -5.562266   2.362240    2.467027    -1.569250   0.703103    2.295304    0.810094    0.232080    0.068292    0.659037    
#> 116: -6.271836   0.207026    -5.771661   2.317987    2.466562    -1.567764   0.735192    2.279674    1.040933    0.220476    0.074169    0.661909    
#> 117: -6.181938   0.247848    -5.916636   2.197798    2.461699    -1.577292   0.724590    2.285703    0.988886    0.221815    0.073582    0.656724    
#> 118: -6.105514   0.259773    -6.031286   2.199732    2.433550    -1.573767   0.713413    2.310808    0.939442    0.227781    0.077772    0.662981    
#> 119: -6.139682   0.230993    -5.775459   2.245673    2.475944    -1.576630   0.720349    2.319870    1.079576    0.255713    0.092191    0.660103    
#> 120: -6.222458   0.265085    -5.780395   2.238269    2.407321    -1.563498   0.717967    2.312104    1.343394    0.242927    0.087581    0.662831    
#> 121: -6.205576   0.292690    -5.818731   2.215492    2.353619    -1.568312   0.708781    2.332225    1.276224    0.237629    0.083202    0.658801    
#> 122: -6.340574   0.248690    -5.792620   2.186040    2.336950    -1.568947   0.751458    2.336919    1.327683    0.225748    0.079042    0.664029    
#> 123: -6.240619   0.286918    -5.922783   2.151440    2.385952    -1.578815   0.739304    2.315010    1.261299    0.239872    0.075090    0.665589    
#> 124: -6.062197   0.188491    -5.671910   2.065987    2.407938    -1.575661   0.754348    2.354000    1.198234    0.258650    0.071335    0.655621    
#> 125: -5.938171   0.133588    -5.669819   2.098894    2.394591    -1.567429   0.766950    2.346589    1.138322    0.245718    0.067769    0.647558    
#> 126: -6.050836   0.159536    -5.575193   2.028379    2.321413    -1.567408   0.759598    2.356169    1.081406    0.233432    0.064380    0.646938    
#> 127: -6.043550   0.162555    -5.630182   2.028261    2.279293    -1.565329   0.757574    2.375814    1.027336    0.221760    0.063550    0.652070    
#> 128: -6.163815   0.156006    -5.713401   2.082449    2.292989    -1.567436   0.783207    2.368118    0.994222    0.210672    0.060373    0.652423    
#> 129: -6.026360   0.134431    -5.730523   2.080405    2.279718    -1.560976   0.774327    2.367867    0.944511    0.207261    0.057354    0.646028    
#> 130: -6.182462   0.182418    -5.854656   2.108885    2.282749    -1.562019   0.772143    2.336400    1.141696    0.206348    0.054486    0.651123    
#> 131: -6.123334   0.226231    -5.956765   2.269243    2.261948    -1.562097   0.764782    2.345229    1.084611    0.203200    0.063076    0.646223    
#> 132: -6.157793   0.253613    -5.899925   2.213909    2.231974    -1.566266   0.763625    2.348024    1.030380    0.193040    0.072373    0.646635    
#> 133: -6.160282   0.176399    -5.600395   2.237008    2.202996    -1.566850   0.759821    2.343707    0.978861    0.200522    0.068755    0.643980    
#> 134: -6.091373   0.214783    -5.522203   2.174087    2.204914    -1.567717   0.766791    2.351139    0.929918    0.190496    0.065317    0.639176    
#> 135: -6.223544   0.196752    -5.619198   2.134648    2.148990    -1.569439   0.762407    2.354880    1.029688    0.189921    0.062051    0.638897    
#> 136: -6.351980   0.222879    -5.619590   1.940290    2.136948    -1.569182   0.777299    2.362702    0.978204    0.180425    0.060331    0.638686    
#> 137: -6.254703   0.238560    -5.325081   1.962909    2.156771    -1.567986   0.778301    2.386634    0.929294    0.197500    0.060935    0.642611    
#> 138: -6.325032   0.223826    -5.596957   1.927149    2.119538    -1.568227   0.777141    2.401026    0.882829    0.208409    0.057888    0.645660    
#> 139: -6.327387   0.252262    -5.794480   1.837559    2.130708    -1.571525   0.771579    2.385050    0.849735    0.205737    0.054994    0.648003    
#> 140: -6.315469   0.252960    -5.515650   1.918284    2.087438    -1.569570   0.765491    2.393909    1.066001    0.200785    0.052244    0.650808    
#> 141: -6.259260   0.196768    -5.359083   1.898649    2.102203    -1.572031   0.760099    2.389715    1.012701    0.190746    0.054229    0.650098    
#> 142: -6.286116   0.207886    -5.429603   1.828356    2.113582    -1.568979   0.760490    2.398108    1.040263    0.210455    0.051517    0.644076    
#> 143: -6.277863   0.144409    -5.400326   1.798129    2.124122    -1.568783   0.766750    2.390298    1.135030    0.199932    0.083070    0.640880    
#> 144: -6.097191   0.152707    -5.265616   1.784166    2.067682    -1.569320   0.775770    2.387152    1.078278    0.189935    0.081843    0.640220    
#> 145: -6.030562   0.169422    -5.372859   1.638945    2.042808    -1.571701   0.782241    2.388795    1.024364    0.182802    0.079024    0.646379    
#> 146: -5.929208   0.183166    -5.215155   1.582296    2.124695    -1.572587   0.799206    2.384018    0.973146    0.173661    0.080349    0.649840    
#> 147: -6.091094   0.148861    -5.413417   1.518910    2.117711    -1.577794   0.803974    2.390770    1.018066    0.189119    0.076332    0.651413    
#> 148: -6.038322   0.163040    -5.364643   1.405403    2.060034    -1.580065   0.800919    2.394011    0.967163    0.199397    0.075860    0.643081    
#> 149: -6.144971   0.162795    -5.434824   1.639964    2.046322    -1.578302   0.788771    2.397330    0.918804    0.189427    0.100187    0.642488    
#> 150: -6.158308   0.153766    -5.322483   1.715597    2.019627    -1.577785   0.777469    2.393026    0.872864    0.179956    0.095178    0.642393    
#> 151: -6.325919   0.162711    -5.333445   1.774397    1.980282    -1.576951   0.764681    2.393685    0.924791    0.177011    0.090419    0.640315    
#> 152: -6.275873   0.140045    -5.434571   1.728362    1.946403    -1.579603   0.779750    2.395632    0.947999    0.177398    0.074118    0.640285    
#> 153: -6.388154   0.204051    -5.674642   1.587373    1.920670    -1.577911   0.790669    2.395030    0.973367    0.198067    0.059956    0.633047    
#> 154: -6.392683   0.185443    -5.801330   1.582848    1.964034    -1.578287   0.793954    2.392946    1.015318    0.204812    0.070121    0.631243    
#> 155: -6.318437   0.228441    -5.918381   1.503735    1.936745    -1.577975   0.794713    2.391426    0.593669    0.212431    0.062457    0.635381    
#> 156: -6.244482   0.191055    -5.744870   1.600130    1.955168    -1.577474   0.795110    2.391378    0.654095    0.239660    0.058790    0.636975    
#> 157: -6.280873   0.176652    -5.640207   1.532814    1.973167    -1.579682   0.792470    2.391740    0.693335    0.222825    0.054457    0.642161    
#> 158: -6.347095   0.192369    -5.639766   1.674537    1.995592    -1.580147   0.791439    2.396190    0.803920    0.212944    0.051899    0.642383    
#> 159: -6.316945   0.133937    -5.675075   1.639609    1.976042    -1.579965   0.785751    2.394868    0.984798    0.193061    0.052124    0.642193    
#> 160: -6.196957   0.133609    -5.674684   1.679991    1.981697    -1.580074   0.785797    2.393723    0.826229    0.196067    0.071522    0.636361    
#> 161: -6.158592   0.155390    -5.689167   1.712191    2.025802    -1.580988   0.784514    2.392092    0.581564    0.166288    0.073511    0.634819    
#> 162: -6.137448   0.154718    -5.678096   1.699526    2.025256    -1.580696   0.782306    2.393472    0.572338    0.162702    0.065574    0.636686    
#> 163: -6.100945   0.148876    -5.661370   1.590237    2.003860    -1.582737   0.776825    2.392300    0.717984    0.148697    0.056941    0.645844    
#> 164: -6.169722   0.144153    -5.675152   1.588790    2.007761    -1.583089   0.780865    2.393946    0.791595    0.180963    0.062668    0.639522    
#> 165: -6.165415   0.136011    -5.468960   1.626551    2.036934    -1.584196   0.776216    2.391671    0.953662    0.223472    0.055287    0.653602    
#> 166: -6.168184   0.169013    -5.549479   1.658533    2.018651    -1.584383   0.776294    2.390741    1.047761    0.222250    0.050838    0.653822    
#> 167: -6.228627   0.220283    -5.594599   1.565492    2.028183    -1.583950   0.781883    2.391679    1.008091    0.206021    0.035260    0.641002    
#> 168: -6.313146   0.222538    -5.916894   1.534677    2.032115    -1.584270   0.784079    2.390755    1.151038    0.223107    0.030725    0.645640    
#> 169: -6.245363   0.215022    -5.951179   1.528584    2.022510    -1.584000   0.785383    2.389286    0.970954    0.219767    0.032126    0.647806    
#> 170: -6.147276   0.130025    -5.557288   1.601452    2.020010    -1.584146   0.787341    2.386905    0.940890    0.185054    0.031372    0.650503    
#> 171: -6.189950   0.113086    -5.714958   1.737105    2.031047    -1.584089   0.782702    2.386961    1.128114    0.135486    0.036217    0.647351    
#> 172: -6.221322   0.102054    -5.701951   1.781948    2.055567    -1.583864   0.781344    2.387267    1.214306    0.128140    0.033982    0.652524    
#> 173: -6.375344   0.146202    -5.820274   1.867366    2.078362    -1.583308   0.788934    2.388403    1.604321    0.132159    0.027481    0.653632    
#> 174: -6.317145   0.145986    -5.704583   1.950026    2.081375    -1.583737   0.794455    2.389226    1.069156    0.151687    0.024780    0.645972    
#> 175: -6.354248   0.193550    -5.778465   1.889422    2.079067    -1.583930   0.799495    2.388396    1.196044    0.158432    0.027334    0.655684    
#> 176: -6.474609   0.164674    -5.288514   1.896971    2.095629    -1.584153   0.802286    2.389881    1.636644    0.176902    0.025370    0.642049    
#> 177: -6.481511   0.194558    -5.409854   1.920877    2.108349    -1.583950   0.800018    2.388218    1.798048    0.155473    0.027795    0.651002    
#> 178: -6.236869   0.174708    -5.611176   1.800213    2.116938    -1.583644   0.802930    2.386063    1.219576    0.140254    0.032773    0.649996    
#> 179: -6.402773   0.160141    -5.504130   1.821194    2.150982    -1.583531   0.807279    2.384348    1.661895    0.128963    0.034756    0.648968    
#> 180: -6.200352   0.201573    -5.379617   1.622757    2.098665    -1.583212   0.808068    2.384942    1.291450    0.136027    0.034760    0.648252    
#> 181: -6.154629   0.134022    -5.703647   1.517957    2.097937    -1.583226   0.808596    2.384396    1.267142    0.109287    0.038464    0.653541    
#> 182: -6.017586   0.152084    -5.624867   1.590407    2.115783    -1.582320   0.809266    2.382520    0.877975    0.112818    0.049803    0.646338    
#> 183: -6.035195   0.155852    -5.615884   1.541263    2.122084    -1.582177   0.812211    2.383690    1.082328    0.138553    0.063931    0.643350    
#> 184: -6.030149   0.160561    -5.709429   1.547401    2.114630    -1.581728   0.814090    2.381816    0.915867    0.133825    0.054102    0.644647    
#> 185: -6.104584   0.163207    -5.562519   1.570250    2.105220    -1.582416   0.815267    2.381782    0.914228    0.115981    0.058587    0.651388    
#> 186: -6.083656   0.135009    -5.728530   1.448787    2.091375    -1.582231   0.812878    2.382702    1.109141    0.121905    0.049311    0.642822    
#> 187: -6.043931   0.169513    -5.766415   1.324844    2.099793    -1.581689   0.812464    2.383573    1.185721    0.131987    0.028303    0.653313    
#> 188: -6.248159   0.200303    -5.861558   1.228064    2.095785    -1.580921   0.814914    2.382313    1.274920    0.189190    0.025971    0.655708    
#> 189: -6.216796   0.232604    -6.067062   1.177817    2.121533    -1.581297   0.814820    2.380523    0.890098    0.128944    0.026408    0.657238    
#> 190: -6.051454   0.196362    -5.895573   1.255496    2.123353    -1.581410   0.814494    2.380912    0.935833    0.110422    0.029227    0.663242    
#> 191: -5.991635   0.211124    -5.892124   1.298279    2.106945    -1.580958   0.817877    2.382479    0.892656    0.156577    0.024955    0.655780    
#> 192: -6.047691   0.215289    -5.783624   1.295377    2.101948    -1.580537   0.822596    2.383478    0.727932    0.177825    0.023867    0.652239    
#> 193: -6.058464   0.208433    -5.788977   1.327596    2.102704    -1.579820   0.820865    2.383558    0.693397    0.190835    0.021649    0.648304    
#> 194: -6.127456   0.199013    -5.709657   1.387952    2.107181    -1.579817   0.821016    2.384216    1.010959    0.157728    0.016798    0.643460    
#> 195: -6.227061   0.196115    -5.660851   1.380943    2.065294    -1.579715   0.824801    2.383256    0.925967    0.197993    0.010805    0.639466    
#> 196: -6.266126   0.189600    -5.536753   1.370643    2.057695    -1.579833   0.823964    2.384284    0.846838    0.197563    0.010803    0.647238    
#> 197: -6.115913   0.236366    -5.580681   1.288545    2.072621    -1.579683   0.822335    2.384590    0.802606    0.166022    0.009784    0.655001    
#> 198: -6.208735   0.238806    -5.787343   1.374681    2.085660    -1.579910   0.823466    2.385170    0.827327    0.160943    0.007928    0.655151    
#> 199: -6.026800   0.172341    -5.542369   1.381131    2.078567    -1.579377   0.829612    2.386308    0.707425    0.132404    0.009525    0.657788    
#> 200: -6.065896   0.195934    -5.843292   1.245720    2.077078    -1.579436   0.835513    2.386421    0.703542    0.153531    0.010915    0.654184    
#> 201: -6.037815   0.179665    -5.856646   1.228126    2.079716    -1.579472   0.834502    2.386669    0.695206    0.146807    0.010431    0.652812    
#> 202: -6.028586   0.181602    -5.843096   1.212655    2.070687    -1.579546   0.834535    2.386968    0.657706    0.159442    0.009587    0.649653    
#> 203: -6.044318   0.180826    -5.858661   1.217956    2.062988    -1.579690   0.835442    2.387093    0.672605    0.162923    0.009638    0.648720    
#> 204: -6.046978   0.181294    -5.894891   1.237035    2.059972    -1.579767   0.836940    2.386929    0.685689    0.160335    0.009125    0.649360    
#> 205: -6.043055   0.182333    -5.884985   1.239171    2.058677    -1.579866   0.837564    2.386514    0.723288    0.160096    0.008652    0.648540    
#> 206: -6.036032   0.181109    -5.852392   1.233912    2.057789    -1.579925   0.838107    2.386205    0.738081    0.162979    0.008352    0.648612    
#> 207: -6.021484   0.174248    -5.818854   1.226714    2.058142    -1.579931   0.838259    2.386064    0.739126    0.167603    0.008222    0.649271    
#> 208: -6.021153   0.178548    -5.781242   1.217706    2.058278    -1.579969   0.837869    2.385988    0.734650    0.170048    0.008390    0.648289    
#> 209: -6.024589   0.179765    -5.779787   1.212574    2.058043    -1.580034   0.837517    2.385894    0.726853    0.174663    0.008344    0.647845    
#> 210: -6.030079   0.175771    -5.780179   1.204973    2.058852    -1.580046   0.837288    2.385857    0.734415    0.176820    0.008288    0.648433    
#> 211: -6.040055   0.177450    -5.794317   1.198500    2.057909    -1.580059   0.837219    2.385841    0.739096    0.178775    0.008551    0.648061    
#> 212: -6.035596   0.178451    -5.827752   1.192430    2.057509    -1.580042   0.837034    2.385903    0.734221    0.178636    0.008799    0.648304    
#> 213: -6.029890   0.179485    -5.830050   1.203492    2.056636    -1.580063   0.836721    2.385927    0.726448    0.178199    0.008916    0.648118    
#> 214: -6.033296   0.179384    -5.832462   1.208809    2.055636    -1.580080   0.836647    2.386086    0.737925    0.175812    0.009218    0.648277    
#> 215: -6.030611   0.179355    -5.827819   1.207980    2.054422    -1.580124   0.837061    2.386209    0.735468    0.173543    0.009301    0.648179    
#> 216: -6.035382   0.179111    -5.815675   1.207442    2.053668    -1.580101   0.836748    2.386266    0.731987    0.174308    0.009478    0.647885    
#> 217: -6.035829   0.176307    -5.811447   1.208206    2.053912    -1.580079   0.836504    2.386225    0.735263    0.176265    0.009634    0.647785    
#> 218: -6.038716   0.175212    -5.803094   1.206385    2.053257    -1.580077   0.836465    2.386161    0.733623    0.176340    0.009662    0.647668    
#> 219: -6.041517   0.175288    -5.801713   1.201899    2.052986    -1.580071   0.836203    2.386120    0.742767    0.174339    0.009691    0.647549    
#> 220: -6.043059   0.176269    -5.796338   1.200782    2.052814    -1.580064   0.835774    2.386176    0.746294    0.174218    0.009577    0.647663    
#> 221: -6.036313   0.173807    -5.789282   1.197929    2.052883    -1.580060   0.835830    2.386210    0.747214    0.173470    0.009509    0.647661    
#> 222: -6.032821   0.173200    -5.789147   1.197023    2.053001    -1.580068   0.836058    2.386252    0.748097    0.173701    0.009505    0.647812    
#> 223: -6.036244   0.174542    -5.792903   1.198885    2.051814    -1.580075   0.836298    2.386294    0.747196    0.173818    0.009628    0.647757    
#> 224: -6.041139   0.175180    -5.793230   1.200699    2.050583    -1.580088   0.836439    2.386350    0.749775    0.173900    0.009679    0.648171    
#> 225: -6.043020   0.175228    -5.791977   1.202539    2.049128    -1.580091   0.836605    2.386423    0.746513    0.172858    0.009645    0.648319    
#> 226: -6.046010   0.176542    -5.800956   1.206747    2.049049    -1.580100   0.836478    2.386463    0.740736    0.172758    0.009670    0.648484    
#> 227: -6.047372   0.177541    -5.797073   1.208294    2.048999    -1.580110   0.836630    2.386540    0.735427    0.173241    0.009569    0.648499    
#> 228: -6.046613   0.179333    -5.790336   1.209323    2.048665    -1.580151   0.836746    2.386574    0.734800    0.173869    0.009545    0.648611    
#> 229: -6.044694   0.178995    -5.787903   1.204573    2.048612    -1.580161   0.836807    2.386575    0.737819    0.173179    0.009451    0.648555    
#> 230: -6.042447   0.179510    -5.784850   1.201315    2.048126    -1.580167   0.836830    2.386646    0.737473    0.172945    0.009373    0.648470    
#> 231: -6.039397   0.178523    -5.791924   1.197328    2.047892    -1.580168   0.837007    2.386696    0.733809    0.172560    0.009365    0.648534    
#> 232: -6.036427   0.178179    -5.789821   1.196629    2.048126    -1.580190   0.837114    2.386712    0.731822    0.172685    0.009345    0.648553    
#> 233: -6.033091   0.177061    -5.799356   1.194444    2.048561    -1.580205   0.837205    2.386745    0.731844    0.173215    0.009316    0.648459    
#> 234: -6.031825   0.177946    -5.802713   1.196768    2.049599    -1.580209   0.837133    2.386682    0.729929    0.173644    0.009350    0.648295    
#> 235: -6.034125   0.178225    -5.803463   1.196937    2.050089    -1.580215   0.837158    2.386677    0.738386    0.173230    0.009321    0.648398    
#> 236: -6.033578   0.178278    -5.803268   1.197542    2.050695    -1.580205   0.836972    2.386695    0.740681    0.173695    0.009310    0.648269    
#> 237: -6.031523   0.177823    -5.807296   1.197821    2.051536    -1.580196   0.836803    2.386713    0.738362    0.174924    0.009297    0.648264    
#> 238: -6.032938   0.178312    -5.804907   1.199093    2.052565    -1.580187   0.836730    2.386708    0.741566    0.174679    0.009273    0.648278    
#> 239: -6.036625   0.178590    -5.802814   1.200676    2.053060    -1.580198   0.836685    2.386695    0.748088    0.174349    0.009254    0.648200    
#> 240: -6.038614   0.178476    -5.805921   1.199476    2.052806    -1.580209   0.836699    2.386687    0.751567    0.173535    0.009186    0.648094    
#> 241: -6.039377   0.179273    -5.802644   1.201012    2.053554    -1.580221   0.836574    2.386679    0.755957    0.173417    0.009161    0.648230    
#> 242: -6.038992   0.178773    -5.800146   1.200837    2.053305    -1.580236   0.836671    2.386614    0.756825    0.173937    0.009164    0.648202    
#> 243: -6.037900   0.177973    -5.805214   1.201441    2.053442    -1.580241   0.836707    2.386597    0.750510    0.174491    0.009193    0.648137    
#> 244: -6.040853   0.178040    -5.806775   1.200190    2.053385    -1.580238   0.836878    2.386595    0.752354    0.174600    0.009297    0.648071    
#> 245: -6.041440   0.177158    -5.807770   1.198658    2.053476    -1.580236   0.836873    2.386585    0.755209    0.174053    0.009363    0.648010    
#> 246: -6.040935   0.176217    -5.809667   1.193594    2.053928    -1.580223   0.836785    2.386542    0.756366    0.173823    0.009379    0.648088    
#> 247: -6.042686   0.176416    -5.814321   1.193132    2.054173    -1.580211   0.836709    2.386513    0.759862    0.173311    0.009408    0.648109    
#> 248: -6.043405   0.176550    -5.819465   1.192699    2.054664    -1.580192   0.836713    2.386501    0.765463    0.172159    0.009460    0.648017    
#> 249: -6.043893   0.177021    -5.824353   1.192617    2.055544    -1.580199   0.836803    2.386499    0.763867    0.171985    0.009560    0.648053    
#> 250: -6.044945   0.177262    -5.819880   1.194029    2.056006    -1.580193   0.836721    2.386489    0.765597    0.171627    0.009683    0.647954    
#> 251: -6.047887   0.177378    -5.820870   1.195264    2.056631    -1.580186   0.836656    2.386486    0.771218    0.171941    0.009698    0.648057    
#> 252: -6.048612   0.177427    -5.823707   1.194988    2.057101    -1.580191   0.836783    2.386541    0.772344    0.172590    0.009635    0.647889    
#> 253: -6.049066   0.177827    -5.825395   1.194089    2.057479    -1.580196   0.837006    2.386538    0.774513    0.172940    0.009634    0.647771    
#> 254: -6.049048   0.178839    -5.826311   1.193668    2.057369    -1.580210   0.836932    2.386556    0.774409    0.173425    0.009584    0.647762    
#> 255: -6.048001   0.179124    -5.827309   1.192610    2.057279    -1.580221   0.836922    2.386566    0.771649    0.174069    0.009614    0.647635    
#> 256: -6.047107   0.178913    -5.826684   1.193528    2.057428    -1.580223   0.836962    2.386578    0.771121    0.174244    0.009592    0.647521    
#> 257: -6.048364   0.179067    -5.832659   1.192514    2.057655    -1.580227   0.836982    2.386577    0.769778    0.174925    0.009565    0.647441    
#> 258: -6.049405   0.178953    -5.836710   1.192253    2.057754    -1.580233   0.837061    2.386589    0.770680    0.174636    0.009540    0.647455    
#> 259: -6.050180   0.179745    -5.836728   1.191039    2.057760    -1.580242   0.837214    2.386570    0.772053    0.174236    0.009477    0.647323    
#> 260: -6.049428   0.179666    -5.835383   1.191068    2.057765    -1.580256   0.837334    2.386555    0.770341    0.174152    0.009441    0.647381    
#> 261: -6.051605   0.179912    -5.836785   1.190800    2.057749    -1.580263   0.837337    2.386565    0.771234    0.174262    0.009441    0.647680    
#> 262: -6.052710   0.180040    -5.837382   1.191502    2.057984    -1.580270   0.837338    2.386585    0.774370    0.174398    0.009459    0.647753    
#> 263: -6.053974   0.180336    -5.837455   1.190250    2.057962    -1.580278   0.837275    2.386585    0.774144    0.175086    0.009458    0.647630    
#> 264: -6.054064   0.180412    -5.837370   1.189923    2.057767    -1.580283   0.837224    2.386604    0.772050    0.175621    0.009481    0.647624    
#> 265: -6.053364   0.180051    -5.838664   1.189542    2.057349    -1.580276   0.837090    2.386607    0.771275    0.175555    0.009413    0.647627    
#> 266: -6.053209   0.179397    -5.839791   1.189392    2.057116    -1.580270   0.837089    2.386608    0.770433    0.174799    0.009360    0.647701    
#> 267: -6.051532   0.178090    -5.842313   1.189751    2.056841    -1.580266   0.837161    2.386618    0.767936    0.174527    0.009323    0.647705    
#> 268: -6.050828   0.177429    -5.840276   1.189344    2.056821    -1.580268   0.837191    2.386622    0.767327    0.174388    0.009331    0.647681    
#> 269: -6.049406   0.177114    -5.837303   1.188262    2.056895    -1.580266   0.837178    2.386643    0.764614    0.174535    0.009306    0.647585    
#> 270: -6.049433   0.177187    -5.830595   1.188201    2.056686    -1.580265   0.837200    2.386646    0.764728    0.174772    0.009310    0.647612    
#> 271: -6.049443   0.177363    -5.831428   1.188125    2.056419    -1.580271   0.837225    2.386656    0.765160    0.174783    0.009325    0.647655    
#> 272: -6.051996   0.178100    -5.830547   1.188394    2.056143    -1.580272   0.837242    2.386657    0.766096    0.174963    0.009286    0.647686    
#> 273: -6.053571   0.178575    -5.832195   1.188197    2.056127    -1.580269   0.837184    2.386657    0.767302    0.175488    0.009238    0.647795    
#> 274: -6.056184   0.179485    -5.835056   1.188628    2.055770    -1.580266   0.837159    2.386661    0.768545    0.176191    0.009206    0.647853    
#> 275: -6.057057   0.179438    -5.834413   1.188943    2.055673    -1.580272   0.837111    2.386649    0.768505    0.176338    0.009184    0.647834    
#> 276: -6.057962   0.178982    -5.833021   1.190094    2.055464    -1.580269   0.837097    2.386646    0.768050    0.176209    0.009204    0.647776    
#> 277: -6.058703   0.178756    -5.833162   1.189989    2.055481    -1.580268   0.837103    2.386654    0.766992    0.176468    0.009223    0.647724    
#> 278: -6.059102   0.178395    -5.834376   1.190078    2.055408    -1.580267   0.837177    2.386656    0.764714    0.177226    0.009204    0.647745    
#> 279: -6.057286   0.177536    -5.833635   1.190416    2.055383    -1.580268   0.837201    2.386671    0.763163    0.177514    0.009195    0.647823    
#> 280: -6.057668   0.177602    -5.832522   1.191050    2.055035    -1.580268   0.837163    2.386690    0.762942    0.177939    0.009196    0.648017    
#> 281: -6.057448   0.177591    -5.831519   1.191456    2.054938    -1.580265   0.837136    2.386702    0.763840    0.178164    0.009177    0.647994    
#> 282: -6.057426   0.177837    -5.829458   1.192467    2.054967    -1.580265   0.837145    2.386697    0.766685    0.177837    0.009146    0.648047    
#> 283: -6.057274   0.177812    -5.828143   1.193473    2.055194    -1.580266   0.837172    2.386704    0.766852    0.177680    0.009163    0.648082    
#> 284: -6.056543   0.177530    -5.828204   1.193807    2.055465    -1.580265   0.837165    2.386715    0.766715    0.177692    0.009141    0.648147    
#> 285: -6.057796   0.177368    -5.827359   1.194291    2.055632    -1.580263   0.837151    2.386712    0.767489    0.177905    0.009125    0.648220    
#> 286: -6.056816   0.176908    -5.827372   1.194164    2.055920    -1.580265   0.837189    2.386715    0.767285    0.178143    0.009144    0.648354    
#> 287: -6.056175   0.176334    -5.827578   1.194194    2.056145    -1.580267   0.837262    2.386719    0.766393    0.178137    0.009158    0.648389    
#> 288: -6.056441   0.176516    -5.828566   1.193477    2.056228    -1.580270   0.837354    2.386718    0.764927    0.178744    0.009165    0.648437    
#> 289: -6.058400   0.176810    -5.828672   1.193913    2.056237    -1.580272   0.837374    2.386716    0.764114    0.178813    0.009161    0.648486    
#> 290: -6.060409   0.177255    -5.827538   1.194646    2.056333    -1.580274   0.837377    2.386716    0.764562    0.179031    0.009147    0.648570    
#> 291: -6.060679   0.177193    -5.825811   1.194235    2.056358    -1.580276   0.837342    2.386721    0.764426    0.179092    0.009117    0.648646    
#> 292: -6.060304   0.176963    -5.825061   1.194517    2.056542    -1.580276   0.837317    2.386719    0.764202    0.179245    0.009085    0.648572    
#> 293: -6.059629   0.176429    -5.825661   1.194346    2.056700    -1.580278   0.837306    2.386719    0.764391    0.178857    0.009066    0.648610    
#> 294: -6.059987   0.176295    -5.824778   1.194817    2.056676    -1.580279   0.837332    2.386726    0.765443    0.178739    0.009074    0.648613    
#> 295: -6.061109   0.176425    -5.826245   1.195581    2.056675    -1.580278   0.837325    2.386732    0.766450    0.178804    0.009101    0.648772    
#> 296: -6.062310   0.176179    -5.827352   1.196032    2.056804    -1.580278   0.837293    2.386740    0.767684    0.179088    0.009115    0.648824    
#> 297: -6.063260   0.176214    -5.828144   1.195971    2.056936    -1.580276   0.837302    2.386736    0.767862    0.179344    0.009153    0.648854    
#> 298: -6.063789   0.176357    -5.827673   1.196394    2.056891    -1.580278   0.837327    2.386728    0.768145    0.179817    0.009125    0.648987    
#> 299: -6.064205   0.176159    -5.827665   1.196184    2.057022    -1.580280   0.837328    2.386725    0.767278    0.180212    0.009118    0.648982    
#> 300: -6.063257   0.175864    -5.827706   1.195928    2.057239    -1.580281   0.837306    2.386723    0.767917    0.179755    0.009094    0.649096    
#> 301: -6.063963   0.175417    -5.827506   1.196154    2.057201    -1.580281   0.837273    2.386713    0.769572    0.179628    0.009082    0.649142    
#> 302: -6.064292   0.174989    -5.827463   1.195917    2.057216    -1.580282   0.837255    2.386715    0.771041    0.179851    0.009086    0.649162    
#> 303: -6.065281   0.175079    -5.827874   1.195542    2.057290    -1.580282   0.837222    2.386715    0.772002    0.180495    0.009080    0.649111    
#> 304: -6.066031   0.175445    -5.827980   1.194970    2.057348    -1.580283   0.837203    2.386710    0.771087    0.180828    0.009083    0.649185    
#> 305: -6.066728   0.175550    -5.828371   1.195149    2.057141    -1.580282   0.837195    2.386715    0.769650    0.181103    0.009084    0.649273    
#> 306: -6.066555   0.175765    -5.827260   1.195322    2.057172    -1.580285   0.837174    2.386718    0.769288    0.180810    0.009086    0.649373    
#> 307: -6.066312   0.175838    -5.826478   1.195334    2.057111    -1.580284   0.837147    2.386726    0.770957    0.180264    0.009081    0.649494    
#> 308: -6.067659   0.175986    -5.826741   1.195422    2.057049    -1.580283   0.837118    2.386728    0.771725    0.180197    0.009100    0.649578    
#> 309: -6.068875   0.175607    -5.826290   1.195720    2.057057    -1.580284   0.837104    2.386727    0.772746    0.180148    0.009082    0.649652    
#> 310: -6.069327   0.175429    -5.827419   1.195983    2.056916    -1.580283   0.837124    2.386724    0.773253    0.180170    0.009061    0.649749    
#> 311: -6.071000   0.175214    -5.827659   1.196453    2.056900    -1.580282   0.837119    2.386724    0.774159    0.180513    0.009085    0.649809    
#> 312: -6.074942   0.175568    -5.827848   1.196635    2.056893    -1.580280   0.837108    2.386723    0.777990    0.180673    0.009087    0.649991    
#> 313: -6.077020   0.175466    -5.828379   1.196787    2.056811    -1.580276   0.837090    2.386721    0.782056    0.180356    0.009095    0.650238    
#> 314: -6.077813   0.175686    -5.828444   1.196532    2.056751    -1.580276   0.837074    2.386725    0.783074    0.180264    0.009099    0.650399    
#> 315: -6.078419   0.175724    -5.828864   1.196629    2.056473    -1.580277   0.837054    2.386720    0.781925    0.180084    0.009100    0.650539    
#> 316: -6.078243   0.175286    -5.829453   1.196758    2.056541    -1.580276   0.837034    2.386720    0.781681    0.180067    0.009101    0.650599    
#> 317: -6.077354   0.175082    -5.829594   1.196830    2.056561    -1.580276   0.837005    2.386718    0.781178    0.179934    0.009086    0.650763    
#> 318: -6.078394   0.175126    -5.830734   1.197140    2.056532    -1.580276   0.836999    2.386719    0.782015    0.180161    0.009091    0.650991    
#> 319: -6.078994   0.174825    -5.830709   1.197440    2.056751    -1.580278   0.836994    2.386718    0.783338    0.180342    0.009091    0.651111    
#> 320: -6.078722   0.174449    -5.831040   1.197470    2.057027    -1.580279   0.836994    2.386720    0.782489    0.180331    0.009092    0.651213    
#> 321: -6.079064   0.174437    -5.831676   1.197376    2.057171    -1.580279   0.836982    2.386720    0.782364    0.180845    0.009078    0.651353    
#> 322: -6.080840   0.174540    -5.832640   1.197239    2.057164    -1.580278   0.836955    2.386721    0.785828    0.180890    0.009069    0.651475    
#> 323: -6.081529   0.174380    -5.834011   1.196861    2.057252    -1.580279   0.836944    2.386720    0.788400    0.181074    0.009091    0.651630    
#> 324: -6.081900   0.174392    -5.835389   1.196590    2.057373    -1.580280   0.836936    2.386716    0.789000    0.181314    0.009124    0.651712    
#> 325: -6.082667   0.174088    -5.837475   1.196511    2.057462    -1.580281   0.836939    2.386715    0.790673    0.181340    0.009155    0.651787    
#> 326: -6.083294   0.173871    -5.839127   1.196273    2.057714    -1.580282   0.836930    2.386713    0.791467    0.181211    0.009158    0.651891    
#> 327: -6.084230   0.173938    -5.840173   1.195935    2.057873    -1.580284   0.836915    2.386713    0.792885    0.181126    0.009170    0.652037    
#> 328: -6.084604   0.173845    -5.841502   1.195788    2.058130    -1.580285   0.836916    2.386712    0.793185    0.180720    0.009160    0.652217    
#> 329: -6.085434   0.173819    -5.842126   1.195706    2.058175    -1.580286   0.836887    2.386712    0.794439    0.180548    0.009158    0.652371    
#> 330: -6.086003   0.173672    -5.843371   1.195737    2.058235    -1.580287   0.836868    2.386708    0.795014    0.180510    0.009145    0.652514    
#> 331: -6.086434   0.173781    -5.844106   1.195800    2.058287    -1.580288   0.836866    2.386704    0.795323    0.180489    0.009137    0.652618    
#> 332: -6.086570   0.173309    -5.845219   1.196107    2.058212    -1.580290   0.836867    2.386703    0.795779    0.180370    0.009129    0.652714    
#> 333: -6.087548   0.173305    -5.846386   1.196440    2.058193    -1.580291   0.836874    2.386701    0.795284    0.180352    0.009159    0.652782    
#> 334: -6.088154   0.173063    -5.846765   1.196665    2.058296    -1.580291   0.836872    2.386699    0.794973    0.180655    0.009190    0.652891    
#> 335: -6.088465   0.173118    -5.847050   1.196799    2.058661    -1.580291   0.836871    2.386697    0.795671    0.180681    0.009238    0.653021    
#> 336: -6.088392   0.173090    -5.847709   1.196950    2.058844    -1.580292   0.836866    2.386695    0.794775    0.180643    0.009277    0.653192    
#> 337: -6.089316   0.173286    -5.848658   1.196894    2.059079    -1.580293   0.836848    2.386694    0.793864    0.180809    0.009286    0.653409    
#> 338: -6.090231   0.173594    -5.849502   1.196900    2.059419    -1.580292   0.836838    2.386694    0.794475    0.181080    0.009305    0.653552    
#> 339: -6.090790   0.173772    -5.850307   1.196937    2.059704    -1.580293   0.836845    2.386694    0.793953    0.181163    0.009341    0.653762    
#> 340: -6.091524   0.173708    -5.850852   1.197127    2.059737    -1.580292   0.836852    2.386695    0.795821    0.181104    0.009352    0.653986    
#> 341: -6.093583   0.173634    -5.852101   1.197156    2.059691    -1.580293   0.836857    2.386695    0.801092    0.180756    0.009367    0.654131    
#> 342: -6.095329   0.173581    -5.853323   1.197093    2.059677    -1.580293   0.836861    2.386697    0.805043    0.180648    0.009363    0.654359    
#> 343: -6.096139   0.173497    -5.854044   1.197042    2.059594    -1.580293   0.836868    2.386699    0.806763    0.180475    0.009353    0.654567    
#> 344: -6.097481   0.173515    -5.854938   1.196970    2.059392    -1.580293   0.836874    2.386698    0.808511    0.180374    0.009357    0.654756    
#> 345: -6.098826   0.173461    -5.855573   1.197049    2.059177    -1.580293   0.836870    2.386697    0.810282    0.180272    0.009352    0.654916    
#> 346: -6.099580   0.173645    -5.856468   1.197044    2.059152    -1.580293   0.836864    2.386698    0.812035    0.180058    0.009350    0.655130    
#> 347: -6.100172   0.173749    -5.857303   1.196936    2.059309    -1.580293   0.836859    2.386697    0.813129    0.180190    0.009351    0.655346    
#> 348: -6.100944   0.173606    -5.857872   1.196896    2.059371    -1.580294   0.836859    2.386696    0.816074    0.180351    0.009333    0.655551    
#> 349: -6.101458   0.173568    -5.858367   1.196887    2.059371    -1.580294   0.836846    2.386696    0.816761    0.180302    0.009337    0.655757    
#> 350: -6.102804   0.173572    -5.859193   1.196853    2.059304    -1.580294   0.836836    2.386695    0.818264    0.180365    0.009348    0.656007    
#> 351: -6.104791   0.173801    -5.859258   1.196882    2.059309    -1.580294   0.836820    2.386695    0.822139    0.180277    0.009375    0.656187    
#> 352: -6.106087   0.174053    -5.859334   1.196883    2.059223    -1.580294   0.836820    2.386696    0.822448    0.180278    0.009364    0.656362    
#> 353: -6.106770   0.173900    -5.859721   1.196853    2.059240    -1.580294   0.836825    2.386698    0.821934    0.180446    0.009381    0.656548    
#> 354: -6.107426   0.173984    -5.860248   1.196877    2.059368    -1.580294   0.836828    2.386699    0.821918    0.180865    0.009381    0.656733    
#> 355: -6.108138   0.174113    -5.860629   1.196969    2.059441    -1.580295   0.836831    2.386698    0.823038    0.180795    0.009395    0.656959    
#> 356: -6.108404   0.174174    -5.861406   1.197054    2.059530    -1.580294   0.836836    2.386697    0.822943    0.180596    0.009404    0.657120    
#> 357: -6.108877   0.174093    -5.861779   1.197079    2.059590    -1.580294   0.836834    2.386698    0.823159    0.180446    0.009408    0.657302    
#> 358: -6.108763   0.173932    -5.862791   1.196975    2.059704    -1.580294   0.836834    2.386698    0.823043    0.180195    0.009393    0.657505    
#> 359: -6.108732   0.173967    -5.863424   1.197018    2.059771    -1.580295   0.836840    2.386698    0.823419    0.180162    0.009391    0.657751    
#> 360: -6.109942   0.174047    -5.863960   1.197041    2.059871    -1.580295   0.836846    2.386698    0.824655    0.180121    0.009382    0.657998    
#> 361: -6.111187   0.174529    -5.864635   1.196936    2.059896    -1.580294   0.836850    2.386698    0.825532    0.180048    0.009371    0.658219    
#> 362: -6.112350   0.174840    -5.865256   1.196929    2.059929    -1.580294   0.836857    2.386697    0.827003    0.179934    0.009360    0.658434    
#> 363: -6.114102   0.175022    -5.865708   1.196969    2.059881    -1.580294   0.836854    2.386698    0.828675    0.179605    0.009355    0.658633    
#> 364: -6.114782   0.175159    -5.866213   1.196941    2.059826    -1.580294   0.836856    2.386699    0.828047    0.179563    0.009366    0.658791    
#> 365: -6.115472   0.175249    -5.867194   1.197043    2.059777    -1.580294   0.836856    2.386700    0.827486    0.179740    0.009374    0.659018    
#> 366: -6.116723   0.175305    -5.868093   1.197034    2.059806    -1.580294   0.836864    2.386700    0.827939    0.179718    0.009381    0.659287    
#> 367: -6.118015   0.175355    -5.868623   1.196983    2.059828    -1.580294   0.836869    2.386699    0.828761    0.179685    0.009384    0.659532    
#> 368: -6.119776   0.175627    -5.869040   1.196933    2.059834    -1.580294   0.836866    2.386700    0.830846    0.179849    0.009369    0.659779    
#> 369: -6.121534   0.176057    -5.869051   1.196896    2.059831    -1.580293   0.836863    2.386700    0.832659    0.179995    0.009351    0.659987    
#> 370: -6.122019   0.175997    -5.869564   1.196877    2.059989    -1.580293   0.836864    2.386700    0.832322    0.180110    0.009350    0.660181    
#> 371: -6.122684   0.175957    -5.869990   1.196850    2.060024    -1.580294   0.836862    2.386700    0.832180    0.180233    0.009342    0.660412    
#> 372: -6.123321   0.175811    -5.870265   1.196823    2.060100    -1.580293   0.836863    2.386699    0.832969    0.180303    0.009341    0.660702    
#> 373: -6.125075   0.176070    -5.870562   1.196833    2.060072    -1.580293   0.836867    2.386699    0.836367    0.180286    0.009353    0.660910    
#> 374: -6.126267   0.176255    -5.871124   1.196805    2.060173    -1.580293   0.836866    2.386699    0.839078    0.180160    0.009364    0.661131    
#> 375: -6.127959   0.176680    -5.871373   1.196842    2.060157    -1.580293   0.836870    2.386698    0.841202    0.180125    0.009383    0.661356    
#> 376: -6.129673   0.177089    -5.872011   1.196822    2.060142    -1.580293   0.836870    2.386697    0.842788    0.180090    0.009401    0.661564    
#> 377: -6.131429   0.177355    -5.872411   1.196874    2.060121    -1.580293   0.836872    2.386697    0.845215    0.179833    0.009408    0.661743    
#> 378: -6.132754   0.177368    -5.872805   1.196915    2.060110    -1.580293   0.836870    2.386696    0.846563    0.179758    0.009451    0.661912    
#> 379: -6.133762   0.177410    -5.873260   1.196992    2.060206    -1.580293   0.836868    2.386696    0.848371    0.179577    0.009466    0.662095    
#> 380: -6.134338   0.177342    -5.873345   1.197032    2.060309    -1.580293   0.836865    2.386696    0.850785    0.179277    0.009467    0.662290    
#> 381: -6.135501   0.177564    -5.873448   1.196968    2.060399    -1.580293   0.836859    2.386695    0.853946    0.179073    0.009462    0.662489    
#> 382: -6.136397   0.177847    -5.873716   1.196910    2.060423    -1.580293   0.836857    2.386694    0.855726    0.179073    0.009471    0.662719    
#> 383: -6.137161   0.177858    -5.874207   1.196919    2.060457    -1.580293   0.836857    2.386693    0.858043    0.179168    0.009472    0.662931    
#> 384: -6.137219   0.177761    -5.874653   1.196958    2.060603    -1.580292   0.836857    2.386693    0.858753    0.179163    0.009476    0.663153    
#> 385: -6.138451   0.178104    -5.874775   1.196967    2.060686    -1.580293   0.836855    2.386693    0.859541    0.179169    0.009463    0.663399    
#> 386: -6.139182   0.177998    -5.875010   1.196973    2.060818    -1.580292   0.836852    2.386694    0.859719    0.179125    0.009460    0.663630    
#> 387: -6.139428   0.178177    -5.875211   1.196938    2.060923    -1.580292   0.836852    2.386694    0.859764    0.179052    0.009453    0.663859    
#> 388: -6.139561   0.178218    -5.875550   1.196970    2.060993    -1.580292   0.836850    2.386694    0.860798    0.178854    0.009470    0.664097    
#> 389: -6.140247   0.178272    -5.876004   1.197022    2.061058    -1.580293   0.836851    2.386693    0.862558    0.178709    0.009462    0.664348    
#> 390: -6.140819   0.178336    -5.876475   1.197081    2.061152    -1.580293   0.836851    2.386693    0.863234    0.178583    0.009475    0.664577    
#> 391: -6.142423   0.178440    -5.876900   1.197080    2.061289    -1.580293   0.836850    2.386693    0.865048    0.178452    0.009505    0.664795    
#> 392: -6.143787   0.178602    -5.877018   1.197081    2.061398    -1.580293   0.836850    2.386692    0.866582    0.178507    0.009511    0.665024    
#> 393: -6.144871   0.178722    -5.877099   1.197104    2.061459    -1.580293   0.836849    2.386692    0.868765    0.178422    0.009520    0.665251    
#> 394: -6.144994   0.178652    -5.877345   1.197072    2.061425    -1.580293   0.836847    2.386692    0.868791    0.178364    0.009533    0.665504    
#> 395: -6.145551   0.178788    -5.877386   1.197057    2.061347    -1.580293   0.836845    2.386692    0.868717    0.178285    0.009544    0.665774    
#> 396: -6.146122   0.178946    -5.877413   1.197063    2.061320    -1.580293   0.836848    2.386692    0.869142    0.178089    0.009546    0.666037    
#> 397: -6.145799   0.179001    -5.877612   1.197070    2.061295    -1.580293   0.836850    2.386692    0.868917    0.177956    0.009551    0.666323    
#> 398: -6.145435   0.178883    -5.877766   1.197048    2.061314    -1.580292   0.836850    2.386692    0.868514    0.177910    0.009539    0.666586    
#> 399: -6.145462   0.178975    -5.877899   1.197007    2.061444    -1.580293   0.836851    2.386693    0.868424    0.177735    0.009539    0.666833    
#> 400: -6.145058   0.179045    -5.877900   1.196988    2.061540    -1.580292   0.836848    2.386692    0.868677    0.177788    0.009542    0.667075    
#> 401: -6.145929   0.179370    -5.877934   1.196991    2.061566    -1.580292   0.836848    2.386692    0.870083    0.177713    0.009543    0.667305    
#> 402: -6.146705   0.179472    -5.878118   1.197008    2.061634    -1.580292   0.836847    2.386692    0.870916    0.177513    0.009546    0.667512    
#> 403: -6.147052   0.179507    -5.878108   1.196991    2.061536    -1.580292   0.836848    2.386692    0.871450    0.177380    0.009542    0.667749    
#> 404: -6.147439   0.179502    -5.878152   1.196961    2.061486    -1.580292   0.836849    2.386692    0.870963    0.177192    0.009540    0.668005    
#> 405: -6.148872   0.179571    -5.878141   1.196958    2.061559    -1.580292   0.836849    2.386692    0.872419    0.176999    0.009533    0.668235    
#> 406: -6.149616   0.179602    -5.878109   1.196963    2.061706    -1.580292   0.836849    2.386692    0.873656    0.176962    0.009529    0.668445    
#> 407: -6.150745   0.179548    -5.878181   1.197021    2.061733    -1.580291   0.836848    2.386692    0.875736    0.177017    0.009511    0.668696    
#> 408: -6.152057   0.179614    -5.878206   1.197060    2.061787    -1.580291   0.836847    2.386692    0.876787    0.177122    0.009493    0.668959    
#> 409: -6.152907   0.179679    -5.878269   1.197066    2.061828    -1.580291   0.836847    2.386692    0.877639    0.177037    0.009510    0.669191    
#> 410: -6.153211   0.179743    -5.878329   1.197069    2.061731    -1.580291   0.836847    2.386693    0.877610    0.176870    0.009518    0.669482    
#> 411: -6.154053   0.179854    -5.878413   1.197053    2.061627    -1.580291   0.836845    2.386693    0.877629    0.176622    0.009508    0.669717    
#> 412: -6.154495   0.179887    -5.878600   1.197058    2.061530    -1.580291   0.836845    2.386693    0.877304    0.176533    0.009495    0.669959    
#> 413: -6.155504   0.180021    -5.878722   1.197081    2.061466    -1.580291   0.836844    2.386693    0.878849    0.176532    0.009507    0.670183    
#> 414: -6.156257   0.180234    -5.878737   1.197091    2.061474    -1.580291   0.836845    2.386693    0.880300    0.176613    0.009525    0.670395    
#> 415: -6.157630   0.180359    -5.878791   1.197106    2.061513    -1.580291   0.836845    2.386692    0.881421    0.176836    0.009533    0.670575    
#> 416: -6.158151   0.180682    -5.878840   1.197115    2.061490    -1.580291   0.836846    2.386692    0.881584    0.177025    0.009531    0.670785    
#> 417: -6.159223   0.180914    -5.878827   1.197114    2.061459    -1.580291   0.836847    2.386693    0.881917    0.176890    0.009543    0.671019    
#> 418: -6.160714   0.181202    -5.879019   1.197139    2.061475    -1.580291   0.836846    2.386693    0.883315    0.177017    0.009521    0.671212    
#> 419: -6.162107   0.181335    -5.879189   1.197155    2.061568    -1.580291   0.836846    2.386693    0.884814    0.176974    0.009514    0.671446    
#> 420: -6.163023   0.181595    -5.879221   1.197141    2.061631    -1.580291   0.836846    2.386693    0.885840    0.176835    0.009501    0.671652    
#> 421: -6.163378   0.181839    -5.879217   1.197128    2.061777    -1.580291   0.836847    2.386693    0.885780    0.176739    0.009503    0.671901    
#> 422: -6.163771   0.182005    -5.879175   1.197152    2.061916    -1.580291   0.836847    2.386693    0.885581    0.176690    0.009504    0.672121    
#> 423: -6.164718   0.182121    -5.879384   1.197165    2.061966    -1.580291   0.836848    2.386692    0.886795    0.176612    0.009506    0.672339    
#> 424: -6.164925   0.181878    -5.879565   1.197185    2.061924    -1.580291   0.836850    2.386693    0.887431    0.176430    0.009510    0.672570    
#> 425: -6.165348   0.181904    -5.879662   1.197232    2.061947    -1.580291   0.836850    2.386693    0.888161    0.176160    0.009502    0.672801    
#> 426: -6.165820   0.182066    -5.879694   1.197257    2.061949    -1.580291   0.836851    2.386693    0.888357    0.176192    0.009488    0.673030    
#> 427: -6.166490   0.182272    -5.879682   1.197287    2.062022    -1.580291   0.836849    2.386692    0.888447    0.176075    0.009485    0.673340    
#> 428: -6.167066   0.182693    -5.879685   1.197295    2.062091    -1.580291   0.836847    2.386692    0.889431    0.175840    0.009487    0.673586    
#> 429: -6.167569   0.182839    -5.879752   1.197279    2.062132    -1.580291   0.836846    2.386692    0.889514    0.175718    0.009492    0.673774    
#> 430: -6.168188   0.182904    -5.879848   1.197276    2.062090    -1.580291   0.836847    2.386692    0.889279    0.175665    0.009502    0.673962    
#> 431: -6.169256   0.183025    -5.879826   1.197262    2.062136    -1.580291   0.836847    2.386692    0.889977    0.175652    0.009508    0.674146    
#> 432: -6.169799   0.183043    -5.879832   1.197251    2.062179    -1.580291   0.836848    2.386692    0.890746    0.175726    0.009519    0.674342    
#> 433: -6.171019   0.183080    -5.879886   1.197253    2.062111    -1.580291   0.836847    2.386692    0.892795    0.175585    0.009525    0.674527    
#> 434: -6.171730   0.182909    -5.880017   1.197256    2.062039    -1.580291   0.836847    2.386692    0.894755    0.175482    0.009526    0.674720    
#> 435: -6.172819   0.182984    -5.879975   1.197276    2.062015    -1.580291   0.836848    2.386692    0.896099    0.175325    0.009517    0.674922    
#> 436: -6.173393   0.183071    -5.880058   1.197257    2.062058    -1.580291   0.836847    2.386692    0.896909    0.175101    0.009517    0.675102    
#> 437: -6.174209   0.183222    -5.880144   1.197266    2.062064    -1.580291   0.836847    2.386692    0.897442    0.174937    0.009530    0.675302    
#> 438: -6.175162   0.183554    -5.880142   1.197250    2.062152    -1.580291   0.836847    2.386692    0.898984    0.174830    0.009532    0.675500    
#> 439: -6.175614   0.183697    -5.880175   1.197256    2.062320    -1.580291   0.836846    2.386692    0.898876    0.174789    0.009551    0.675659    
#> 440: -6.176162   0.184060    -5.880090   1.197247    2.062343    -1.580291   0.836846    2.386693    0.899166    0.174724    0.009562    0.675842    
#> 441: -6.176646   0.184162    -5.880063   1.197232    2.062358    -1.580291   0.836846    2.386693    0.898976    0.174798    0.009565    0.676046    
#> 442: -6.177091   0.184350    -5.880082   1.197219    2.062396    -1.580291   0.836846    2.386693    0.898716    0.174735    0.009560    0.676243    
#> 443: -6.177304   0.184469    -5.880130   1.197223    2.062376    -1.580291   0.836846    2.386693    0.898474    0.174740    0.009544    0.676433    
#> 444: -6.177979   0.184653    -5.880119   1.197244    2.062441    -1.580291   0.836846    2.386693    0.899919    0.174669    0.009524    0.676598    
#> 445: -6.179327   0.184709    -5.880164   1.197258    2.062410    -1.580291   0.836845    2.386693    0.901296    0.174705    0.009513    0.676764    
#> 446: -6.180538   0.184884    -5.880229   1.197261    2.062440    -1.580291   0.836845    2.386693    0.902108    0.174730    0.009505    0.676955    
#> 447: -6.181524   0.185152    -5.880232   1.197242    2.062434    -1.580291   0.836846    2.386693    0.902555    0.174573    0.009507    0.677146    
#> 448: -6.181977   0.185336    -5.880225   1.197245    2.062467    -1.580291   0.836846    2.386693    0.903022    0.174478    0.009499    0.677310    
#> 449: -6.182526   0.185462    -5.880183   1.197244    2.062539    -1.580291   0.836846    2.386693    0.904547    0.174330    0.009505    0.677510    
#> 450: -6.182784   0.185534    -5.880244   1.197254    2.062657    -1.580291   0.836846    2.386693    0.904591    0.174204    0.009517    0.677681    
#> 451: -6.182754   0.185583    -5.880271   1.197261    2.062817    -1.580291   0.836847    2.386693    0.904089    0.174101    0.009532    0.677868    
#> 452: -6.183551   0.185804    -5.880360   1.197260    2.062911    -1.580291   0.836847    2.386693    0.903807    0.174118    0.009544    0.678058    
#> 453: -6.184528   0.186019    -5.880356   1.197251    2.062976    -1.580291   0.836847    2.386693    0.904310    0.174051    0.009537    0.678243    
#> 454: -6.185329   0.186176    -5.880404   1.197271    2.063050    -1.580291   0.836847    2.386693    0.903861    0.174140    0.009526    0.678400    
#> 455: -6.186111   0.186385    -5.880416   1.197267    2.063051    -1.580291   0.836847    2.386693    0.904025    0.174133    0.009511    0.678582    
#> 456: -6.186933   0.186661    -5.880432   1.197261    2.063071    -1.580291   0.836847    2.386693    0.904163    0.174035    0.009504    0.678751    
#> 457: -6.187594   0.186814    -5.880443   1.197264    2.063124    -1.580291   0.836847    2.386693    0.904756    0.174213    0.009499    0.678916    
#> 458: -6.187833   0.186925    -5.880423   1.197271    2.063245    -1.580291   0.836848    2.386693    0.905474    0.174193    0.009489    0.679067    
#> 459: -6.188186   0.187009    -5.880417   1.197279    2.063305    -1.580291   0.836848    2.386693    0.906362    0.174159    0.009473    0.679239    
#> 460: -6.188835   0.187154    -5.880444   1.197274    2.063328    -1.580291   0.836848    2.386693    0.906750    0.174187    0.009461    0.679387    
#> 461: -6.188948   0.187371    -5.880464   1.197265    2.063374    -1.580291   0.836850    2.386693    0.906941    0.174048    0.009462    0.679561    
#> 462: -6.189564   0.187509    -5.880440   1.197270    2.063329    -1.580291   0.836849    2.386693    0.907676    0.173916    0.009469    0.679725    
#> 463: -6.190448   0.187587    -5.880441   1.197271    2.063329    -1.580291   0.836850    2.386693    0.908502    0.173872    0.009466    0.679868    
#> 464: -6.191483   0.187701    -5.880423   1.197266    2.063374    -1.580291   0.836850    2.386693    0.910099    0.173762    0.009477    0.680031    
#> 465: -6.191756   0.187716    -5.880443   1.197268    2.063375    -1.580291   0.836850    2.386693    0.910741    0.173583    0.009484    0.680203    
#> 466: -6.192128   0.187945    -5.880462   1.197272    2.063466    -1.580291   0.836851    2.386693    0.910617    0.173468    0.009496    0.680363    
#> 467: -6.191922   0.187986    -5.880462   1.197265    2.063485    -1.580291   0.836850    2.386694    0.911220    0.173283    0.009502    0.680564    
#> 468: -6.192252   0.188121    -5.880465   1.197268    2.063575    -1.580291   0.836851    2.386693    0.912097    0.173186    0.009509    0.680744    
#> 469: -6.192807   0.188083    -5.880455   1.197263    2.063700    -1.580291   0.836851    2.386693    0.913243    0.172981    0.009521    0.680925    
#> 470: -6.193546   0.188353    -5.880434   1.197273    2.063757    -1.580291   0.836851    2.386693    0.914142    0.172986    0.009528    0.681071    
#> 471: -6.194452   0.188554    -5.880468   1.197277    2.063826    -1.580291   0.836851    2.386693    0.914835    0.172966    0.009525    0.681231    
#> 472: -6.194954   0.188785    -5.880463   1.197277    2.063924    -1.580291   0.836850    2.386693    0.915274    0.172895    0.009533    0.681370    
#> 473: -6.195435   0.188911    -5.880493   1.197276    2.063962    -1.580291   0.836851    2.386693    0.915866    0.172796    0.009543    0.681511    
#> 474: -6.195670   0.189023    -5.880503   1.197272    2.063964    -1.580291   0.836851    2.386693    0.916550    0.172677    0.009551    0.681684    
#> 475: -6.195548   0.189017    -5.880527   1.197284    2.064029    -1.580291   0.836851    2.386693    0.916422    0.172827    0.009558    0.681829    
#> 476: -6.195939   0.189132    -5.880514   1.197285    2.064093    -1.580291   0.836851    2.386693    0.916113    0.173001    0.009559    0.681970    
#> 477: -6.196285   0.189300    -5.880506   1.197286    2.064137    -1.580291   0.836851    2.386693    0.916195    0.173037    0.009554    0.682134    
#> 478: -6.196794   0.189424    -5.880502   1.197295    2.064253    -1.580291   0.836851    2.386693    0.916532    0.173020    0.009558    0.682283    
#> 479: -6.197305   0.189458    -5.880503   1.197302    2.064222    -1.580291   0.836851    2.386693    0.916986    0.172824    0.009552    0.682427    
#> 480: -6.197515   0.189553    -5.880513   1.197302    2.064361    -1.580291   0.836852    2.386693    0.917864    0.172647    0.009570    0.682563    
#> 481: -6.197319   0.189526    -5.880549   1.197303    2.064397    -1.580291   0.836852    2.386693    0.917497    0.172473    0.009572    0.682717    
#> 482: -6.197479   0.189246    -5.880568   1.197303    2.064415    -1.580291   0.836851    2.386693    0.917853    0.172456    0.009571    0.682878    
#> 483: -6.198094   0.189202    -5.880576   1.197300    2.064436    -1.580291   0.836851    2.386693    0.918094    0.172321    0.009579    0.683033    
#> 484: -6.198382   0.189400    -5.880546   1.197304    2.064482    -1.580291   0.836851    2.386693    0.918337    0.172155    0.009588    0.683176    
#> 485: -6.199007   0.189562    -5.880550   1.197308    2.064467    -1.580291   0.836852    2.386693    0.918739    0.172011    0.009588    0.683330    
#> 486: -6.199466   0.189584    -5.880568   1.197314    2.064401    -1.580291   0.836852    2.386693    0.918423    0.171895    0.009587    0.683461    
#> 487: -6.200135   0.189629    -5.880574   1.197317    2.064334    -1.580291   0.836852    2.386693    0.918636    0.171781    0.009595    0.683593    
#> 488: -6.200577   0.189829    -5.880561   1.197316    2.064251    -1.580291   0.836852    2.386693    0.919075    0.171611    0.009605    0.683714    
#> 489: -6.201068   0.190060    -5.880585   1.197313    2.064314    -1.580291   0.836852    2.386693    0.920265    0.171515    0.009605    0.683839    
#> 490: -6.201465   0.190254    -5.880614   1.197319    2.064358    -1.580291   0.836852    2.386693    0.920794    0.171382    0.009615    0.683986    
#> 491: -6.202337   0.190338    -5.880630   1.197318    2.064367    -1.580291   0.836852    2.386693    0.922308    0.171253    0.009623    0.684113    
#> 492: -6.202564   0.190382    -5.880622   1.197314    2.064366    -1.580291   0.836852    2.386693    0.921999    0.171198    0.009645    0.684249    
#> 493: -6.203172   0.190543    -5.880638   1.197317    2.064325    -1.580291   0.836853    2.386693    0.922254    0.171084    0.009656    0.684387    
#> 494: -6.203512   0.190569    -5.880659   1.197320    2.064366    -1.580291   0.836853    2.386693    0.922135    0.171025    0.009664    0.684514    
#> 495: -6.204128   0.190650    -5.880655   1.197325    2.064434    -1.580291   0.836853    2.386693    0.923104    0.171044    0.009664    0.684658    
#> 496: -6.204598   0.190819    -5.880648   1.197317    2.064495    -1.580291   0.836853    2.386693    0.923249    0.171073    0.009657    0.684797    
#> 497: -6.204884   0.190909    -5.880661   1.197316    2.064589    -1.580291   0.836853    2.386693    0.923414    0.171080    0.009651    0.684930    
#> 498: -6.205137   0.190943    -5.880657   1.197310    2.064630    -1.580291   0.836853    2.386693    0.923029    0.170945    0.009653    0.685066    
#> 499: -6.205292   0.191066    -5.880633   1.197302    2.064681    -1.580291   0.836853    2.386693    0.922783    0.170733    0.009649    0.685234    
#> 500: -6.205790   0.191033    -5.880628   1.197297    2.064696    -1.580291   0.836853    2.386693    0.923242    0.170624    0.009641    0.685365    
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Goodness of fit Plots

## Add cwres/npde after fit
fit  <- fit %>% addCwres() %>% addNpde()
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plot(fit) ## Standard nlmixr plots


################################################################################
## Xpose plots; Need to print otherwise running a script won't
## show xpose plots
################################################################################
xpdb <- xpose_data_nlmixr(fit) ## first convert to nlmixr object

print(dv_vs_pred(xpdb) +
      ylab("Observed Nimotuzumab Concentrations (ug/mL)") +
      xlab("Population Predicted Nimotuzumab Concentrations (ug/mL)"))


print(dv_vs_ipred(xpdb) +
      ylab("Observed Nimotuzumab Concentrations (ug/mL)") +
      xlab("Individual Predicted Nimotuzumab Concentrations (ug/mL)"))


print(res_vs_pred(xpdb) +
      ylab("Conditional Weighted Residuals") +
      xlab("Population Predicted Nimotuzumab Concentrations (ug/mL)"))


print(res_vs_idv(xpdb) +
      ylab("Conditional Weighted Residuals") +
      xlab("Time (h)"))


print(absval_res_vs_idv(xpdb, res = 'IWRES') +
      ylab("Individual Weighted Residuals") +
      xlab("Time (h)"))


print(absval_res_vs_pred(xpdb, res = 'IWRES') +
      ylab("Individual Weighted Residuals") +
      xlab("Population Predicted Nimotuzumab Concentrations (ug/mL)"))


print(ind_plots(xpdb, nrow=3, ncol=4) +
      ylab("Predicted and Observed Nimotuzumab concentrations (ug/mL)") +
      xlab("Time (h)"))


print(res_distrib(xpdb) +
     ylab("Density") +
     xlab("Conditional Weighted Residuals"))


################################################################################
##Visual Predictive Checks
################################################################################
vpcPlot(fit,n=500,stratify=c("DOS"), show=list(obs_dv=T),
       bins = c(-0.5,0,25,75,100,200,400,600,750,900,1100,1200,1400,1600,1900,2150,2300),
       ylab = "Nimotuzumab Concentrations (ug/mL)", xlab = "Time (h)")


vpcPlot(fit,n=500, show=list(obs_dv=T),
       bins = c(-0.5,0,25,75,100,200,400,600,750,900,1100,1200,1400,1600,1900,2150,2300),
       ylab = "Nimotuzumab Concentrations (ug/mL)", xlab = "Time (h)")