Incidence and mortality of Alzheimer's disease or dementia using an illness-death model.

Texte intégral

(1)Incidence and mortality of Alzheimer’s disease or dementia using an illness-death model. Daniel Commenges, Pierre Joly, Luc Letenneur, Jean-François Dartigues. To cite this version: Daniel Commenges, Pierre Joly, Luc Letenneur, Jean-François Dartigues. Incidence and mortality of Alzheimer’s disease or dementia using an illness-death model.. Statistics in Medicine, Wiley-Blackwell, 2004, 23 (2), pp.199-210. �10.1002/sim.1709�. �inserm-00262112�. HAL Id: inserm-00262112 https://www.hal.inserm.fr/inserm-00262112 Submitted on 11 Mar 2008. HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés..

(2) HAL author manuscript Statistics in Medicine 2004;23(2):199-210. HAL author manuscript. -. .

(3) /

(4). .

(5) 0%132. "! .

(6) . $#&%'()%* +

(7) ,%*. 4%5%768 +

(8) 9/!. ; ! ./ /) =<> 4%5%768 +

(9) 9/! . . : ?@-A . : /B

(10). inserm-00262112, version 1. CED$FHGJIKIMLON1PJLRQTS*UVDXWJGJY[Z7S/\ D]\^LT_`LRN/N1LOa1bcN/deW7fgChcbi_kjlP7a1LRQ mnporqs(t quJvwvJx1SmBorUqC y{z}| bka1L~\hRL GorcjlPJNc8_OSX-Gb`d1LOca*^SrvJvJu} | S/f/bkcN/ {L LOY vJv}HJwJ yJy x7*fXc. vJv7w | z uJuwx y qIcjlYVdcN/jlLRYD RGIKILRN1PJLOQ@j&Qi]LOd^Da*4Gbd1LOca*X5Db /bkjlY^1S]uJuJv. .

(11)

(12) !#"$ %& #')(* %( +(, -.$ /0 &1 (2 3 %$ 4(,(657$ # 80"9:$ 4. HAL author manuscript. ;8<>=-=@?>A B. inserm-00262112, version 1. C DFE+GHDIHDJ#K@LMJONQPRPQJ+D,ISIUTWV8D2LXKHY[Z]\ V+DP_^\

(13) GÌSKba8V8c NRJ+dKHY+DFNRJ+eNRV+DJ+e,D-LMJ+V[KbY8D & E8GHDfXLMPQD,J+eDg\M^ ? PRhY+D,NQZ]DG,ijIkV+NRISD2LMISDl\MGkV+D,ZmD,JKbNRL8nC&D@LXGHd

(14) a+D.KHYLXKoKbY8D NRPRPQJ+D,ISIUT V8D2LXKHYZm\4V+DP:NRIqprDKHKHD,GsKbY+LMJ-LoIHa+GUf NQfXLMP$Z]\ V+DPt^\

(15) GsKbY+NQIE8a+GHEr\

(16) IHDXnvuWJlKbY+NQI_Zm\ V+D,P KHY+D>prD,IUKve7Y8\

(17) NReD^\

(18) GwKbY8D>pLMISNReqKbNQZ]DTWIHe,LMPRDsNQIvLXd

(19) DMnyxsY8D,J.z{D>E+GSD,IHDJKsD6| KbDJ+IHNQ\

(20) J+I{\M^ KHY+NRIZ]\ V+DP#^\MG}NRJ8e,\

(21) GSE/\

(22) GHLXKbNQJ+d_e,\fXLMGHNRLXKbDIyLMJ+V~K7LM#NRJ8dLMe,e\

(23) a+JKw\M^L>E/\MIHIHNQp+PRD{D/D,e6K \X^se2LMPQD,J+V+LMGKHNRZmDMnlLMPQD,J+V+LMGKHNRZmDoNRINRJKbGS\4V+a8e,D,V&f4NRL@L@E+GH\

(24) Er\

(25) GUKbNR\MJLMPyNQJ#KHD,J+ISNQKWc Zm\ V+D,P%n.CD]d

(26) NQfMDmKHY+D`PQNRMDPRNQY+\4\ VF^\

(27) G~L@ZmN)|4D,V&V+NRISe,GHD6KbDTWe,\MJ#KHNRJ#a+\

(28) a8I \

(29) p+ISD,GUfMLKbNR\MJ E+LXKHKHD,GHJ^GS\

(30) ZKHY+NRIkZm\4V8D,Pme,PQNRJ+NQe2LMPISKbLXKba8ImNQIk\

(31) p+ISD,GSfMD,VLXKkV+NQIHe,GSDKHDgf NQIHNQKUTKHNRZmD,I zqY8NRPRDKbY+DVLKbD\M^V+D2LKbYgNRI\Mp+IHDGSf

(32) DVD|+LXeKbP)c \

(33) GGSNRd

(34) YKUTWe,DJ+IH\MGHD,VtnxsY8DE/DJLMPRNQh,DV PQNRXD,PRNQY+\ \4VLME+E+GS\LMe7Y9LMPRPQ\0zqI~Kb\J+\

(35) J4TELMGHLMZ]D6KbGSNRe2LXPRPQcDISKHNRZ]LXKbNQJ+d-KbY+D.KHGbLMJ8IHNQKHNR\

(36) J NQJKbD,J8IHNQKHNRDI,n ? E+E+PQNRe2LKbNR\MJ-\

(37) JFKbY+DoVLK7L.\M^KbY+DmLM#a+NRVISKHa+V8cLXPRPR\zqI>KH\gE+GH\ V+a+eD DISKHNRZ]LXKbDI~\M^vKbY+D]LMd

(38) DTWIHErD,eNQe]NRJ+eNRV+DJ+e,Dm\M^sV8D,ZmD,JKbNRLlKb\Md

(39) DKHY+D,GzqNQKHYZm\

(40) GSKbLMPRN)KWc GHLXKbDIw\M^rp/\XKbYoV+D,ZmD,JKHD,VmLMJ+VoJ+\

(41) J TWV+DZ]DJ#KHD,VoIHa8p SD,e6KbI,nxsY+DJmKHY+DsD/D,e6K\M^/e2LMPQD,J4T V+LMG>KbNQZ]D~LMJ+VFDV+a+e,LXKbNQ\

(42) JLMPPRDfMD,P}LMGHD*IUKba+V8NRD,Vtn~:\zD,V+a+e,LXKbNQ\

(43) JLMP PRD6f

(44) DPyNRJ+eGHD,LMIHDI KHY+DsGHNQIH\M^rV+D,ZmD,JKHNL8nxsY+DsGHNQIH \X^V+D,ZmD,JKbNRLNRJ+eGHD,LMIHDIzqN)KbYke,LMPRDJ+VLMG}KHNRZmD{zqY+NQPRD KHY+DZm\

(45) GSKbLMPRN)KWco\M^$V+D,ZmD,JKHD,VlV+D,eGHD2LXIHD,In{xsY8DZ]\

(46) IUKsPRNQMDPQcmD6|4E+PRLMJLXKHNR\

(47) J.\X^ KHY+NRIvGHD6T ISa+PQK{IHDD,ZmI{KH\ prD>NRJ]L~ISY+NQ^K{NRJoKbY8D>V+NRLMd

(48) J+\

(49) ISNRI\M^:V8D,ZmD,JKbNRLKb\zvLMGHV8IvD2LXGHPRNQD,GISKbLMd

(50) DI \X^yKbY+D V+NRISD2LMISD E+GS\

(51) Z]E4KbD,Vp#cLè7YLXJ+d

(52) D*NQJ@KbY8D ErD,GHeD,E8KHNR\

(53) J\M^V+D,ZmD,JKHNL`LXJ+VKbY8D LXGHGHN)fXLMPt\M^J+D6zV+GHa8d

(54) I,n. `v 6¡~¢v£S¤¥ ? PRh,Y8D,NRZmD,Gi¦IwV8NRIHD,LMIHDX§#V+D,ZmD,JKbNRL8§

(55) NQJ+e,NQV+D,J+eDM§#NRJKHD,GSfXLMP¨TWeD,J+IS\

(56) GHDV V+LXK7L8§ = LMGHX\fgZ]\ V+D,PQI,§+Z a+PQKHN)TWIUK7LXKHD>Zm\4V8D,PRIn. ©.

(57)

(58)

(59) \

(60) GwKHY+DE8a+GHEr\

(61) IHD_\M^tD,ISKHNRZ]LXKbNQJ+dKbY8DNQJ+e,NQV+D,J+eD\X^. HAL author manuscript inserm-00262112, version 1. ? PQh,Y+DNRZmD,Gi¦IV+NQIHD2LXIHD_\

(62) GV+D,ZmD,J4T KHNLkLMJ8V \M^}a8J+V+D,GSISKbLMJ+V+NQJ+dkKbY+DGSD,PLKbNR\MJ+IHY+NQE.prDKWz{D,D,J@NRJ+eNRV+DJ+e,DLXJ+VgE+GHD6fMLXPRD,J8e,DM§ V8NRIHD,LMIHD@\

(63) J+ISDK`LMJ+V[V+D,LXKbY9IHY+\Ma+PRV9p/D*S\

(64) NRJKHPQcZm\4V8D,PRPQD,V a+ISNRJ+dLMJNQPRPRJ8D,IHI TWV+D,LXKbY Zm\ V+D,P%n>xsY+DkLXNRZ \M^wKbY8NRI>E+LME/DGNRI_Kb\.V8D,IHeGHNQp/D*ISa+e7Y L.Z]\ V+DP§Kb\ V+D6f

(65) DPR\

(66) EFIS\

(67) Z]D LXE+E+GH\

(68) LMe7Y+D,I ^\

(69) GÌSK7LKbNRIUKbNQe2LMPNRJ8^DGHD,J8e,DLMJ+VOKH\d

(70) NQfMDFIH\

(71) ZmD-V+DIHe,GSNRE8KHNQfMD DE+NRV8D,ZmN)T \MPR\

(72) d

(73) NQe2LMPsGSD,ISa+PQKHI,n xsY+DFLME8E+GH\LXe7Y[K7LMXD,I NRJKH\LMe,e\

(74) a+JK KbY8D-V+NRISe,GSDKbDELXKHKHD,GSJO\M^ \Mp+IHDGSfXLXKbNQ\

(75) J+Iy^\

(76) GyKHY+Dqe,PQNRJ+NQe2LMP ISKbLXKba+ILMJ8VmNQJf

(77) D,IUKbNQdLXKbDIwKbY+DsEr\

(78) IHISNRp+PQDKbGSD,J+Vm\M^/NRJ+eN)T V8D,J+eD LMJ8V@Zm\

(79) GSKbLMPRN)KWcmGbLXKHD,IszqNQKHYle,LMPRDJ+VLMGKHNRZmDMnyxsY8NRIqELMErD,GqGHDPRNQD,Is\

(80) JgE+GSDf NR\

(81) a8I z{\

(82) GS\

(83) JNRJKHD,GSfXLMPe,DJ+IH\

(84) GSNRJ+d NQJFIHa+GUf NQfXLMPyVLK7L LMJLXPQc IHNQ I T }LMJ+V\

(85) JFZ*a8PQKbNQISKbLXKbD Zm\ V+D,PQ I 0T %nvxsY+D~LMJLMP)c IHNRIq\M^}NRJKbDGSfXLMP¨TWe,DJ+IH\MGHD,V@\

(86) p+ISD,GSfXLXKHNR\

(87) J8Iq^GS\

(88) Z Z*a8PQKbNQISKbLXKbD Zm\ V+D,PQI~zvLMIkISKHa+V+NRDVNRJIS\

(89) ZmD.GHDe,D,JKoz{\

(90) GH T "! $#zvD Y+LfMD d

(91) NQfMD,JGSDf NRD6zqIk\M^ KHY+D,ISDz{\

(92) GS % I T &n uWJ IHD,e6KbNQ\

(93) J © §Z]\ V+D,PQI.zqNQKHY NQJ+e,GSD2LMISNRJ+d IH\ME+Y+NRIUKbNQe2LXKHNR\

(94) J LMGSD E8GHD,ISD,JKbDV[z{D LXGHd

(95) a+D KHYLXK]L ISa+GSf N)fMLXPsZ]\ V+D,PvNRIoJ+\MK]LMVLXE8KbDV KH\ KHY+DgISKba8V8c \M^>V8D,ZmD,JKbNRL&LMJ8V KHYLXK>LÌbLKbNRIU^LMeKH\

(96) GSc ^GHLMZmDz{\

(97) GHgNRIqKbY+LXK>\X^LMJ-NQPRPRJ8D,IHI TWV+D,LXKbYlZm\4V+DPnC&D E+GSD,ISD,JK pr\MKHY L-ISK7LKbNR\MJLMGSc Zm\4V8D,PvNQJzqY+NQe7Y9LXd

(98) D.NRIKbY+D p+LMIHNQe`KbNQZ]DTWIHe,LMPRD]LMJ+V LZm\ V+D,P NQJlzqY8NRe7YKHY+D~KHGbLMJ+ISNQKHNR\

(99) JlNRJKbDJ+IHN)KbNQD,IqZ`L2cgV+DE/DJ+VF\

(100) J@e2LMPQD,J+VLXG_KHNRZmDMnuWJ-ISD,e6KbNR\MJ J (GSD,ISa+PQKHI ' KbY+DlE+GS\

(101) p+PRDZ \M^DISKbNQZ`LKbNR\MJ \X^KbY+DlZm\4V+DPqNRIkKbGSD2LXKHD,VnuWJISD,e6KbNR\M a8IHNRJ8d V+NQ/D,GSD,JKZ]\ V+DPRILME8E+PRNQD,V-Kb\.KHY+DoVLXKbL.\M^KbY+Dm}LX a8NRVISKHa+V8c

(102) § L.e\

(103) Y+\

(104) GUK\M^ ' ) © ISa+p SDeKbI*zqN)KbY c

(105) D,LMGHI \M^s^\

(106) PRPQ\zTWa+E§LMGSDÈ+GSD,IHDJKbD,Vtn A DIHa+P)KbI*a8IHNRJ8d@KbY8D IUK7LXKHNR\

(107) J+LMGScmZm\4V+DPd

(108) NQfMDLMJ.NQV+D2L~\M^:KbY+D>LMd

(109) DTWIHErD,eNQe>NRJ+eNRV+DJ+e,D>LMJ+V.KbY8D>Zm\

(110) GSKbLMPRN)KWc GHLXKbDI`\M^p/\MKHY[V+DZ]DJ#KHD,VOLXJ+V[J+\

(111) J TWV+DZ]DJ#KHD,V[ISa+p SDeKbIn xsY+DJOE/\

(112) ISIHNQp+PRDlD/D,e6K \X^{e,LMPRDJ+VLMG_KbNQZ]D~NRINQJ#fMD,IUKbNRd

(113) LXKbDVn ; D,ELXGbLXKHDoLMJLMP)c4ISD,I^\

(114) GZ]DJLMJ+V-z{\

(115) ZmD,J LMGHD E8GHD,ISD,JKbDVFLMJ+V KHY+DD/D,eK\M^D,V+a8e2LXKHNR\

(116) JLXPPRD6f

(117) D,P:NQIqISKba8V+NRDVn. * =?>A@. + B. -,/.1023 4.

(118) 657.98:;5<

(119) 8 C4DFEHGAIKJ/LNMOPMQOSR/TVUWIUMXGY/TZC\[FGEH]. uWJ]KbD,GSZ \M^:GbLXJ+V+\

(120) Z fXLMGSNLMp+PQDM§KbY8DV+NQISKHGHNRp8a8KbNQ\

(121) J]\X^$LMd

(122) D_\M^:\

(123) J8IHDK_^\M^ ? PRh,Y8D,NRZmD,Gi¦I V8NRIHD,LMIHD`\

(124) G~V8D,ZmD,JKbNRLe2LMJp/D.Zm\ V+D,PQPRD,V`#}KbY+D]YLMh,LMGHVâ8J+eKHNR\

(125) JNQI e\

(126) J+IHNQV+D,GSD,V LMI KHY+D&LMd

(127) D6TIHErD,eNQeNRJ8e,NRV8D,J+eD&\M^~KbY+D V+NQIHD2LXIHDMn uWJ KHY+D ^\MPRPR\zqNQJ+dz{D&zqNRPQP>^\ e,a+ISI \MJ9V+DZ]DJKbNLFGHLXKbY+DG*KbYLXJ ? PRh,Y8D,NRZmD,Gi¦IkV8NRIHD,LMIHDlprD,e2LXa+IHDgKbGSD2LXKHNRJ+d ? PRh,Y8D,NRZmD,Gi¦I V8NRIHD,LMIHD>GbLMNQIHD,I{KbY+DLXV+V+NQKHNR\

(128) J+LMPE+GH\Mp+PRDZ \M^:zqY+LXKKb\ V+\ zqNQKHY.IHa8p SD,e6KbIqV+DfMD,PQ\

(129) E+NRJ8d. '.

(130) \XKbY+DGqKWc ErD,I_\M^V+D,ZmD,JKbNRL8n = \ V+DPRNRJ8dk\M^ \

(131) J+IHD6K_\M^}V8D,ZmD,JKbNRL*e2LMJlp/DE8a8KqNRJ.KHD,GHZmIs\MÎSKH\4e7YLXISKbNQeE+GH\ e,DIHIn \

(132) GoD,LMe7YISa+p SD,e6K zvD@Z`L2cV8DJ+DL&E+GS\4eD,ISI LMI N)ÎHa8p SD,e6K.NRI J8\

(133) J4TWV8D,ZmD,JKbDVLXK § NQÎHa+p#SD,eKV+DZ]DJ#KHD,V@LXK n xsY+DYLMh,LMGHVgâ+J+e6KbNQ\

(134) J ^\

(135) GsIHa+p#SD,eK NRI.

(136) .

(137) . HAL author manuscript. "!#

(138) $ %

(139) PRNRZ !# & 'va4KzqYLXKNRIKbY+DkGS\

(140) PRD*\X^{V8D2LMVIHa8p SD,e6KbI( ? GHD KHY+DcFGSNRd

(141) YKUTWe,DJ+IH\MGHD,V)(OxsY+NRI. inserm-00262112, version 1. E8GH\

(142) p+PQD,Z e2LMJgJ+\MKp/DJ+Dd

(143) PRDeKHD,Vlp/De2LMa+ISD ? PRhY+D,NQZ]DG,ijIV+NQIHD2LXIHDD,ISIHD,JKHNLMPQPQc]\4ee,a+GSI NQJgE/DGHIH\MJ+Iq\

(144) PRV+DGKbYLXJ ! IS\mKHYLXKsKbY8DZm\

(145) GUK7LMPQNQKWcmGbLXKHD,I_LMGSDY8NRd

(146) Y #4NRJ ^LMe6K2§LMIse,LMJ prDISD,D,J ^GS\

(147) Z +d

(148) a+GHDI © LMJ+V ' KHY+Dc.LMGHD>Y+NRd

(149) Y8D,G{KHYLMJ.KHY+DNRJ+eNRV+DJ+e,D>\M^$V+D,ZmD,JKHNL8n _D,GSDvzvDLMGHD{J+\MKyV8D2LMPQNRJ+dqzqNQKHY*ELXKSKbD,GSJ+Iy\M^\Mp+IHDGSfXLXKbNQ\

(150) J+Ip+a8K}zqN)KbY*Zm\ V+D,PQI ^\

(151) G$KbY8D ePRNQJ+NRe,LMPtIUK7LXKHa+I>\M^KbY+DIHa8p SD,e6K2eD,J+IS\

(152) GHNQJ+d]ErD,GUK7LMNQJ+IsKb\oKbY+D\

(153) p+ISD,GUfMLKbNR\MJ@ELKHKbDGHJ§ zqY8NRPRD V8D2LXKHY9NQI]Le,PQNRJ+NQe2LMP{ISKbLXKba+IoJ+\XK]GSD,E+GSD,ISD,JKbDVONRJKbY+NQIoZ]\ V+D,P%nu^V+D,LXKbY NRI KHGHD,LXKbDV9LXIoLeD,J+IS\

(154) GHNQJ+dFfXLMGHNRLMp+PRDX§}KbY8NRI*ZmD2LMJ8I*KbYLXKkz{Dg\

(155) p+ISD,GSfMD ^\

(156) GoL-ISa+p SD,e6K V4c4NQJ+d@zqN)KbY+\Ma8K V8D,ZmD,JKbNRL >KbYLXKKbY8D]KbNQZ]Do\M^\

(157) J+IHD6K \X^sV+D,ZmD,JKHNL@NQI~PRLMGHdMD,GKbYLXJ KHY+D.KbNQZ]D]\M^_V+D2LKbYn va8KkKbY8NRI*YLXIkGHD2LXPRPQc&J+\FZmD2LMJ8NRJ+dFISNRJ+eDgL-IHa+p SDeKozqY+\NRI V8D2LMVe,LMJJ+\MKkV8Df

(158) DPR\

(159) E V+DZ]DJKbNL4n-xsY+D YLMh,LMGHVâ8J+eKHNR\

(160) Jz{\

(161) a+PQVGHDE+GHDIHD,JKoKbY8D GSNRIS@\M^V+D6f

(162) DPR\

(163) E+NQJ+dgV+D,ZmD,JKHNL.Z]LMGHd

(164) NQJLMPQPQc GSD,PLKbNQfMD,P)clKH\.KbY+D*f N)K7LMPISK7LKba+I§$LMJ+VNQK NQIJ+\MKePRD2LXG>zvD6KbY+DGKHY+NRIe,LMJp/DkNQJKbD,GSE+GHD6KbDVLMIKHY+DkNRJ+eNRV+DJ+e,Dk\X^vV+DZ]DJKbNL4n*u^ z{D*zvLMJKKb\ YL2f

(165) DoL.ePRD,LMGHP)c@NQJKbD,GSE+GHD6K7LMp8PRD*Zm\4V8D,P$zvDkZ*a8ISKL2f

(166) \MNRV-KbY8Dke,\

(167) J8â8IHNR\MJ prDKWz{D,DJ9E+LXKHKHD,GHJ\X^q\

(168) p+IHDGSfXLXKHNR\

(169) JLXJ+Ve,PQNRJ+NQe2LMPISKbLXKba8I,n ? J+\XKbY+DG*E/\MNRJK*\M^sf NQDz NQIKbYLKNQ^V+D2LKbY NRIKbGSD2LXKHD,V&LMIe,DJ+IH\

(170) GSNRJ+d8§KbY+DJ&N)KNRILMJNRJ4^\

(171) GHZ]LXKbN)f

(172) D*eD,J+IS\

(173) GHNQJ+d+n xsY8NRI}NQJ8^\

(174) GSZ`LXKHNQfMD,J+DIHI e,\

(175) ZmD,I$^GH\

(176) Z KHY+DvV8NQ/D,GHDJKbNLXP Zm\

(177) GUK7LMPQNQKWcprDKWz{D,DJoV+D,ZmD,JKbDV LXJ+VgJ+\

(178) J4TV+D,ZmD,JKbDVISa+p SD,e6KbILMJ+VlPRD,LMV+IKb\op+NRLMIHDV@DISKHNRZ]LXKbDIs\M^KHY+DLMd

(179) DTWIHErD,eNQe NQJ+e,NQV+D,J8e,DLMIsYLMIqprD,DJIHY8\0zqJ@NRJ M\

(180) P)c.D6K>LXP4 n "! %n. *. ,'. ). +. .-. =?> =. / B. MT10 C:U IAGKGAJ/EOSO2DFEM4365. ] C6DFEHG. 7. uWJ@LMJlNRPQPRJ+DIHIUTV+D2LKbY Zm\4V+DPV+D,LXKbYlNRIsGSD,E+GSD,IHDJKbD,VFD|4E+PRNQe,NQKHPQcmNRJ KHY+D~Zm\ V+D,P%n LMe7Y ISa+p SDeK d

(181) N)f

(182) DI]GSNRIHDgKb\L IUKb\ e7YLMIUKbNRe@E+GH\ e,DIHI *zqY+NRe7Y9K7LMXD,I]KHY+D@fXLMPQa+D N)^ ISa+p SDeKNQI>LMPQNQfMD LMJ8VJ+\MKV+DZ]DJ#KHD,V§ NRI_IHa8p SD,e6KNRILMPRN)f

(183) DLMJ+VV+D,ZmD,JKbDVFLMJ+V © N)^ IHa+p SDeK>NRIsV+D,LMVLKsKbNRZmD IHD% D NRd

(184) a+GSD n xsY+D-KHGbLMJ8IHNQKHNR\

(185) J9NRJKbDJ+IHN)KbNQD,Iè,LMJOprD-e,\

(186) J8IHNRV8D,GHDV LMI Ld

(187) DJ+D,GHLMPRNQIbLXKHNR\

(188) J9\M^KbY8D Y+LMh2LMGSV â8J+eKHNR\

(189) JKbY8Dc#aLMJKbN)^cFKbY+DoGSNRIHF\X^vd

(190) \MNRJ+d ^GH\MZ \

(191) J+DmISKbLXKbDoKb\@LMJ+\MKHY+D,G.

(192) . 8 9. (.

(193)

(194) . L J+V`KbY8Dc.e7Y+LMGbLMe6KbDGHNRhD>KbY8D>Zm\4V+DPn\

(195) GNRJ8ISK7LXJ+e,D>KHY+D>KHGbLMJ+ISNQKHNR\

(196) JmNRJKbDJ+IHN)KWc X ^GS\

(197) Z Y8D2LMP)KbY Kb\mV+D,ZmD,JKHNLkNRIsV+D6J+DV-LMI. HAL author manuscript.

(198) PRNQZ + "!#

(199) %

(200) !# & ; NRZmNRPLXG{V+D6J+N)KbNR\MJ e2LMJlp/Dd

(201) N)f

(202) DJl^\

(203) G

(204) LXJ+V

(205) n _\0z9Kb\ISE/De,NQ^c~KbY+DsZm\ V+D,P8z{DsZ*a+IUKwKbDPRP4zqY+LXKNRI }LMJ+VoY+\z

(206) V8D,ErD,J+Vm\

(207) J Hn C&D_IHYLMPQPe,\

(208) J+ISNRV+DGLGHIUKZm\4V8D,PNRJmzqY+NRe7Y GHDE+GHDIHD,JKHIsLMd

(209) D# KHY+NRIZ]D,LMJ+IKbYLK{^\

(210) G. inserm-00262112, version 1. D,LMe7YÌSa+p SDeKvz{D_e7Y+\4\MIHDKHY+Dq\

(211) GHNQd

(212) NRJk\X^tKbNQZ]DqLXI{prD,NQJ+dV+DJ8D,V.pckKbY8Dp+NQGSKHYm\X^tKbY8D ISa+p SDeK2n_xsY+NQIe7Y+\MNRe,D~NRI_Z]\XKbNQfXLXKHD,VgpcgKbY+D L]E+GSNR\

(213) GSN: J8\0zqPQD,V+dMD~KbY+LXKKHY+D GSNRIS \M^ V8D,ZmD,JKbNRL`LMJ+V-KHY+D Zm\

(214) GUK7LMPQNQKWc GHLXKbDI>D,ISIHDJ#KHNLMPQPQclV+DE/DJ+VF\

(215) JFLMdMD~\M^wKHY+D ISa+p SDeKbIn xsY8D,IHD NRJKbDJ+IHN)KbNRDIqZ`L2cgLMPQIH\mV+D,ErD,J8V-\

(216) Je,LMPRDJ+VLMGsKHNRZmD~LXJ+V@z{D ISYLMPRP:IUKba+V4clKHY+NRI Er\

(217) ISIHNRp8NRPRN)KWcPLXKHD,G #{^\

(218) G KHY+D Zm\

(219) Z]DJK z{DgzqNQPRPe,\

(220) J8IHNRV8D,GoL SIUK7LXKHNR\

(221) JLXGSc FZ]\ V+DPvNRJ zqY8NRe7Y KbY+D>NRJKbDJ+IHN)KbNRDIV+\kJ+\XKV+DE/DJ+V@\MJ e2LMPQD,J+VLXG{KbNQZ]DXn \z PRD6Ka+Ise\

(222) J+IHNQV+D,GL Zm\ V+D,P$NRJlzqY+NRe7Y-KHY+D NQJKbD,J8IHNQKHNRDI\M^LXPRPKbY8D*IHa+p#SD,eKHILMGHDKbY8D*IbLMZmD^\

(223) GKHY+D IHLMZ]D LXd

(224) DM nwxsY+NRIsZ]L2c.YL2fMDKWz{\oNRJKbDGHE+GSDKbLXKbNQ\

(225) J+I,wDNQKHY+D,GvKHY+DIHa+p#SD,eKHI Y+LfMD~GSD2LMPQPQc]KbY+DIbLXZ]DNRJKHD,J+ISNQKbNQD,I GHNRIS#I \

(226) GsKbY+NQIsNRIKHY+D Z`LXGHd

(227) NQJLMP sNQJKbD,J8IHNQKWc.\M^ LkISa+p SD,e6KKbLMMDJ-LXKqGHLMJ+V+\MZ NRJ KbY8DEr\

(228) E+a8PLXKHNR\

(229) Jn xsY+D~e,\

(230) ZmZm\

(231) J \

(232) G_Z`LMGSd

(233) NRJ+LMP KHGbLMJ8IHNQKHNR\

(234) JlNRJKHD,J+ISNQKWc se2LMJ-GSD2LMPQPQc prDe,\

(235) J4T ISNRV+DGHDV LXI`KbY+D NRJ+IUK7LMJKbLMJ+D,\Ma+I .LMdMD6TWISE/De,N)eFNRJ+eNRV+DJ+e,D\M^V+D,ZmD,JKbNRL8n uWJ+V+DD,V e\

(236) J+ISNRV+DGqLoPRLMGHdMD>Er\

(237) E+a+PRLXKbNQ\

(238) J.\M^ IHNQh,D #+KbY+DISa+p SD,e6KbI_\M^$KbY+NQIsE/\ME+a+PLKbNR\MJ`V+\oJ+\MK J8D,D,VKH\-prD`pr\

(239) GHJLK KbY8D.IbLMZmDè,LMPRDJ+VLMGKbNQZ]DmIHNQJ+e,D]zvD LXIHIHa8Z]D]Y+D,GSD`KbYLK KbY8D NQJKbD,J8IHNQKHNRDIV8\~J+\XK{V8D,ErD,J+V]\

(240) J]e,LMPRDJ+VLMGwKHNRZmDMn}xsY8DNQJ+e,NQV+D,J+eD_LXK{LMd

(241) D y^\

(242) GLKbNQZ]D ErD,GSNR\ V e,LMJ.prD>V+D6J+D,VgLXI{KbY8D>J#a+Z*prD,G\X^:J+Dze,LMIHDIV+a+GSNRJ+d 7tV+N)f NRV+DV pc.KHY+DJ#a+Z*prD,Gq\MÊ/DGHIH\MJ+I>LKqGHNRISnz{DYL2f

(243) DX. .

(244)

(245)

(246)

(247) . . . . . . . .

(248) . . !. !. "!7# "! LXK_GHNRIS.LXK $# "! " !#

(249)

(250) #

(251) # "! + * . , / 6 0 2 1 3 , 4 / 0 6 1. 5 \

(252) G% PRLMGHd

(253) DX'&)( !#

(254)

(255)

(256) 6 7 + * 3 , / 8 0 6 1. 5 &3( 6 7

(257) nxsY a8I, 6 7 "!#

(258)

(259)

(260) 6 . "!. J8Dze,LMIHDINQJ. !. . . LMJ8V.

(261) HAL author manuscript. "!#

(262) %

(263) !#

(264) . ! nu^ ! vNRIKHY+DKbNRZmDa+J8NQK2§4^\

(265) GsNRJ+IUK7LMJ8e,D\

(266) J+Dc

(267) D,LMG 2

(268) & NRZmNRPLXGHPQcM§

(269) q LMJ+V

(270) s e2LMJ@p/DNRJKbDGHE+GSDKHD,VFLMILMd

(271) DTWISE/De,NQ+eZm\

(272) GUK7LMPQNQKWc.GHLXKbD. ^\MGsIHZ]LMPRP. ; ^ \MGsJ+\

(273) J4TV+D,ZmD,JKbDVLXJ+V@V8D,ZmD,JKbDVIHa8p SD,e6KbI_GHD,ISE/DeKHNQf

(274) DPQcMn ? d

(275) D6TIHErD,e,N)eE+GHD6fXLMPRDJ+e,D\M^}V+D,ZmD,JKbNRLkNRI. inserm-00262112, version 1. 9. V+DZ]DJ#KHNLk\M^}LMd

(276) D. \MÎHa+p SDeKHI>\M^}LMd

(277) D. &. uWJl\

(278) a+GsZm\ V+D,Pt^\MGqLmPRLMGHd

(279) D>E/\

(280) E8a+PLXKHNR\

(281) J]KbY+NQI_NQIsD,#aLMPKH\+.

(282)

(283) %

(284) ©

(285) © xsY+DÈ+GH\

(286) p+LMp+NRPQNQKHNRD,IKbYLXK NQINQJLld

(287) NQfMD,JIUK7LXKHDè2LXJprD]zqGHN)KHKHD,JNQJ&KHD,GHZmI\M^. KHGbLMJ8IHNQKHNR\

(288) J. NQJKbD,J8IHNQKHNRDI,.

(289)

(290) / 0 / 0

(291) / 0 / 0 / 0 zqY8D,GHD

(292)

(293)

(294) LXGHDKbY8De,a+Z*a8PLXKHNQf

(295) DNQJKbD,J8IHNQKHNRDI#8z{DYL2f

(296) D~LMPRIS\*KbYLXK

(297) ©

(298)

(299) 6 n =?> ! C:UMT IM43SEHO#" 36/ 5 E Y/TZC_Y%C TZ3 IC\J/MXGIAJ S3 EHJ/OVI%3 $ ]NC6DFEHG x Y8D Y+D6KbD,GS\

(300) d

(301) DJ+D,N)KWcprDKWz{D,DJ-KbY+D~IHa+p SDeKHIe2LMJp/D~D6|4E+PLXNRJ+DVNRJlELMGUK>pcl^LMeKH\

(302) GHI s zqY8NRe7Yle2LMJlp/De\4V+DV@pc D|4E+PLMJ+LXKb\

(303) GUc.fXLMGHNRLMp+PQD,I,n}xsY+D,JLodMD,J+DGbLMP:Zm\4V8D,PNQI,.

(304) '&

(305) )(

(306)

(307)

(308)

(309). *(.

(310) . KHYLXK$NQI$KHY+DY+DKHD,GS\

(311) d

(312) D,J8D,NQKWcNQI:D6|4E+PRLMNRJ+DVp#cKHY+DwfXLMPRa+D\M^ §MLfMD,eKH\

(313) G \M^8Er\

(314) ISIHNRp8PQc KHNRZmD6TV+D,ErD,J+V8D,JKD6|4E+PRLMJLXKH\

(315) GSc@fXLMGHNRLMp+PRDIzqY+NQe7Y LMGHD*ISa+E+Er\

(316) IHDV KH\ p/Dke\

(317) ZmE+PRD6KbD,P)c. .

(318)

(319) & . \ p+IHDGSf

(320) DVnuWJgKbYLKe,LMIHDX§KbY+DIHa8p SD,e6KbIISYLMGHDKHY+D~p+LMIHDPRNRJ8Dâ+J+eKHNR\

(321) J8I M sLMJ8V â8J+eKHNR\

(322) J+I zqY+NRe7Y V8DJ+DKHY+D>KWc E/D\X^$Z]\ V+D,PtLMJ+V d

(323) DJ+D,GHLMPRP)cmNRJf

(324) \

(325) P)f

(326) DIqL IHD6Kq\M^ GSD,d

(327) GSD,ISIHNR\MJmE+LMGbLMZmDKHD,GyfMD,eKH\

(328) GHI 6n}xsY8D_Er\

(329) E+a8PLXKHNR\

(330) J*e,LMJmp/DsIHLMNRVoY+\

(331) Zm\

(332) d

(333) DJ+D,\Ma+I,§ e\

(334) J+V+N)KbNQ\

(335) JLMPQPQc~\

(336) J]KHY+D n ? J.LMIHISa+Z]E4KbNR\MJmzqY+NQe7Y.d

(337) GSD2LXKHPQcoIHNQZ]E8PRNQ+D,IyKbY8D Zm\ V+D,Ps^\

(338) GoNRJ4^D,GHDJ+e,DlzqNQKHYe,\MJ#KHNRJ#a+\

(339) a8I]KbNQZ]Dg\

(340) p8IHD,GUfXLXKbNQ\

(341) J+I`NQImKHY+DlE+GH\

(342) Er\

(343) GUKbNR\MJLMP NQJKbD,J8IHNQKWc&LMISIHa+ZmE8KHNR\

(344) J #Le,\

(345) ZmZm\

(346) J&e7Y8\

(347) NReD`NRI. &.

(348) . HAL author manuscript.

(349) (

(350)

(351) ) (

(352)

(353)

(354)

(355) (

(356) / 0

(357) (

(358)

(359) §zqY+D,GSD

(360) NQI]L-fMD,eKH\

(361) Gm\M^GSD,d

(362) GSD,IHISNR\

(363) J e,\ DmeNRD,JKHI,nxsY8D GSD,d

(364) GSD,ISIHNR\MJ[e,\ Dme,NQD,JKbI.LMGHD@NRJE8GHNRJ8e,NRE8PRDgV+NQ/D,GSD,JK`^GS\

(365) Z \

(366) J+DlKbGbLXJ+IHN)KbNR\MJ KH\LMJ4T . \XKbY+DG,§$LMP)KbY+\

(367) a8d

(368) YFIH\

(369) ZmDke,\MJ+ISKHGbLMNQJ#KHIe2LMJprDkE+a8KKb\ E+LMGbLMZmDKHD,GSI,n. inserm-00262112, version 1. =?>. GSD,V+a+eDmKHY+D*Kb\XK7LMPyJ#a+Z p/DG\M^. IA] E 2 O MXGAEO . xsY8D,GHD@LMGSD Z`LMNQJ+PQc KWz{\&\MKHY+D,GkKHNRZmD,I*zqY+NQe7Y9e\

(370) a+PRV NQJ a+DJ+e,DgKbY+D fXLMPQa+D,Ik\M^_KbY8D KHGbLMJ8IHNQKHNR\

(371) JFNQJKbD,J8IHNQKHNRDI,e,LMPRDJ+VLMGKHNRZmDkLMJ+V§^\MGV+D,ZmD,JKbDV§$KbNRZmD*ISNRJ+eDk\

(372) J+IHD6K\M^ V8D,ZmD,JKbNRL8n*xsY+DoZm\

(373) GSKbLMPRN)KWcgGbLXKHDk\M^vV8D,ZmD,JKbDV&ISa+p SD,e6KbI§ §:e,\

(374) a+PQVV+D,ErD,J+V J+\MK \MJ+PQco\

(375) J.LMd

(376) D>p8a8K\

(377) J]KbNRZmDqIHNQJ+e,D\MJ+IHD6K\M^$V+DZ]DJKbNL4 ^ § zqY+D,GSW D ^ NRI KHY+DwKbNQZ]Dy\X^8\

(378) J8IHDK\M^4V+D,ZmD,JKHNL8n xsY#a+I KHY+DZ]\MGSK7LXPRNQKWc_GHLXKbDLXK:KHNRZmD \M^8LqV+D,ZmD,JKbDV ISa+p SDeK dMNQf

(379) DJ]KHYLXKY+D_p/De2LMZmDV8D,ZmD,JKbDV.LXX K ^ }zv\

(380) a8PRV`prD 6n J8D Er\

(381) ISIHNRp8NRPRN)KWc]z{\

(382) a+PQV@prDLmISD,ZmN)TELMGbLXZ]D6KbGHNQeZm\4V+DPa+ISNRJ+d]LmE8GH\

(383) Er\

(384) GSKHNR\

(385) J+LMPtNQJ#KHD,J+ISNQKWc Zm\ V+D,P% n xsY+NRI*Zm\ V+D,PNRI~J+\-Zm\

(386) GHD = LMGHX\fp+a4K ISD,ZmN)T = LMGHX\f #/zvD*zqNQPRP$J+\MKE8a+GHISa+D*KbY+NQI>ELKbYFNRJ@KbY+D ^\MPRPR\zqNQJ+d`LXJ+V-zqNRPQP GSD,Z]LMNRJ NQJ KbY+D^GbLXZ]D6zv\

(387) GS`\M^J+\

(388) J TWY+\

(389) Zm\

(390) d

(391) DJ+D,\Ma+I = LMGHX\fgZ]\ V+D,PQI,n uWJKbDJ+IHN)KbNQD,I*Z]L2c LMPRIS\V+DE/DJ+V \

(392) Je,LMPRDJ+VLMGKbNRZmDMn ; NQJ+e,DmzvD`YL2f

(393) D`KHY+D,JKWz{\ KHNRZmD,IozvDFZ]L2c e7Y+\4\MIHD-\

(394) J8D\

(395) GmKbY+D-\XKbY+DG.LMI.p+LMIHNQe@KbNQZ]DlIHe,LMPRDXn uWJLISD,J+ISDFNQK z{\

(396) a+PQV[prDZm\

(397) GHDlJLXKHa+GbLMPsKH\K7LMXD-LMI]pLMISNRe@KHNRZmDgIHe2LXPRD@KHY+Da8J+NQfMD,GHIHLMP>e,LMPRDJ+VLMG KHNRZmD #Y8\0z{DfMD,GlIHNQJ+e,DFNQJLMPRP_KbY+NQI.ELMErD,GgLMdMD-NRI.KHY+DFZ]\MISK NQZ]Er\

(398) GSKbLMJK]KHNRZmDz{D zqNQPRP MDD,EN)KLMIp+LMIHNQe*KbNRZmD6TIHe,LMPRDX§tISKHNRPQPV+DJ+\MKHD,V p#c n~C&D*zqNRPQP}V+DJ+\MKbDke,LMPRDJ+VLMG KHNRZmDop#c prD,e,LMa+IHD`\M^KbY8D`GHDPLXKHNR\

(399) J8IHY+NQE PQNRJ+#NQJ+dge2LMPQD,J+VLXGKHNRZmD]LXJ+VLMdMDm^\

(400) G ISa+p SDeK H W§ zqY+D,GSD $NQIvKbY8D e2LXPRD,J8VLMG KbNRZmD>\X^p8NRGSKHY.^\

(401) GISa+p SD,e6K wGHDE+GHDIHDJ#KHIsKbY+De2LMPQD,J+VLXG{KbNQZ]DszqY+DJgIHa+p SDeK YLMIsLXd

(402) D n ##KbY#a+I xsY8DKHGbLMJ+ISNQKHNR\

(403) J NQJ#KHD,J+ISNQKHNRD,IsZ]L2c.KbY8D,Jlp/DzqGHN)KHKHD,J §e,\

(404) J+ISNRV+DGHNQJ+dkKbYLXK KHY+D*â+J+e6KbNQ\

(405) J NQIIHYLXGHD,VpcFLXPRP$KbY+DkISa+p SD,e6KbIn ? E+GS\

(406) E/\MGSKbNQ\

(407) JLMP$NQJ#KHD,J+ISNQKWc Zm\ V+D,P

(408) Z]L2cprDwa+IHDV~^\

(409) Gte2LMPQD,J+VLXGKbNRZmDye\

(410) J+IHNQV+D,GSD,V~LMI LKbNRZmD6TV+D,ErD,J8V+D,JK:fXLMGHNRLMp+PQDM. . .

(411) #

(412) -/ 0 .

(413) 4 .

(414) .

(415)

(416) .

(417) . !

(418) .

(419) & & . CN)KbYOKbY+D. . .

(420) "

(421) . -/ 0

(422) "

(423)

(424)

(425)

(426) $# &. E+GS\

(427) E/\MGSKbNQ\

(428) JLMPNRJKbDJ+IHN)KWcOZm\4V+DPRNQJ+dLMJ+V. . prD,e2LXa+IHD. . \M^KbY+D. 8. GHDPLXKHNR\

(429) J.

(430)

(431) . KbY+DE+GS\

(432) p+PQD,Z. fXLMGSNLMp8PRDISNRJ+eDM. e,LMJp/DwISNRZmE+PRN)D,V>KH\_LqZm\ V+D,PMzqN)KbYL8|4D,V~D6|4E+PLXJLXKb\MGSc. HAL author manuscript.

(433)

(434) -

(435)

(436)

(437) "

(438) . Wu J.KHY+DLME8E+PRNQe2LXKHNR\

(439) Jkz{DIHYLXPRPrNRJÈ+LMGSKHNRe,a8PLMGe,\MJ+IHNQV+D,GvL E+GH\ME/\

(440) GUKbNQ\

(441) JLMPNQJ#KHD,J+ISNQKWc Zm\ V+D,PtzqN)KbY 8|4D,V@e,\fXLMGHNRLXKbDI#.

(442)

(443) 8-

(444)

(445)

(446) ( . inserm-00262112, version 1. xsY+NQIE/\MIHIHNQp+NRPQNQKWcl\M^D6|4E+GSD,ISIHNRJ8dlKHY+DoD/D,eK\X^ve,LMPRDJ+VLMG>KHNRZmD*LMIKHY+DoD/D,e6K\M^ p8NRGSKHYVLXKHD.PRD,LMV+I*a+I*KH\FV+NRISe,a+ISIkKbY+D V+NQISKHNRJ+e6KbNR\MJprDKWz{D,D,J9e2LMPQD,J+V+LMG KbNQZ]D]D/D,e6K LXJ+VOe,\

(447) Y8\

(448) GSKgD6tDeK2n LMPQD,J+VLXG.KbNRZmDD6tDeKgISa+Z]Z]LMGSNRh,DI]KHY+DFD/D,e6KbIg\M^^LMeKH\

(449) GHI E8GHD,ISD,JKLXK>e2LMPQD,J+VLXGKbNQZ]D ~ISa+e7Y LMIf NQGHa+ISD,I\

(450) GV+GHa+dMIL2fMLXNRPLXp+PRDLXKKbNRZmD &#tKHY+NRI e,LMJmLMPRIS\prDqLMJ SD/D,e6K V+a+DKH\KbY+DzvL2c*KbY8DsV+NRISD2LMISDsNRIyV+NRLMd

(451) J+\MIHD,VoLKyKbNQZ]D nyxsY8D e\

(452) Y+\

(453) GUKvD6tDeKsZm\

(454) GSDV+NQGHDeKbP)ckGHDPLXKHD,IKb\~KHY+DKHNRZmDq\M^:p+NQGSKbY`LMJ+V`KH\~KHY+D>ISa+p+IHD#a+D,JK D|4E/DGHNRDJ+e,DI ISa+p SD,e6KbI*pr\

(455) GSJLXK Lge,D,GUK7LMNQJ KHNRZmDkYL2f

(456) D]a+J+V+DGSK7LXMD,Jtn \

(457) GNQJ+ISKbLMJ+eD ISa+p SDeKbI pr\

(458) GHJNRJ YL2f

(459) DD6|4ErD,GHNQD,J+eD,VKbY+DwGSISK$zv\MGHPRVzvLMG:zqY+NRPQDyIHa8p SD,e6KbI}pr\

(460) GSJ NQJ '2 YL2fMD]J+\XK #KHY+DcFLMPRIS\lY+LfMD]D|4E/DGHNRDJ+e,DVISPRNRdMY#KHPQc@V+NQ/D,GSD,JKZ]DV+NRe,LMPwLMJ8V DV+a+e,LXKbNQ\

(461) JLMP

(462) IUc ISKbDZ]I V+a+GSNRJ+d_LMPQPXKHY+D,NQG:PRNQ^DI,n ? P)KbY+\Ma+d

(463) YKbY8De\

(464) J+eD,E8KHI}LMGSDwV+NQ/D,GSD,JK2§ KHY+D{KWz{\D/D,e6KbIwLXGHDvNQJ+V+NQISKbNQJ+d

(465) a+NQIHYLXp+PRDNRJKbY+DvE+GH\

(466) Er\

(467) GUKbNR\MJLMPNRJKHD,J+ISNQKWcZ]\ V+DP zqY+DJ LXd

(468) DoNRIKbY+DmpLMISNRekKbNQZ]DTWIHe,LMPRDX§$LMI~LME+ErD2LMGSI^GS\

(469) Z KbY+D]LMpr\f

(470) DmD,#aLXKHNR\

(471) J+In.uWJZ]LMJc Zm\ V+D,PQINQJ+e,PQa+V+NRJ8d>LMdMDKHY+D,GSDNRI PRN)KHKbPQDNRJ8^\

(472) GSZ`LKbNR\MJ§0LMPQKHY+\

(473) a+dMY~KbY8D,GHD{e,\

(474) a8PRV*prDvIS\

(475) Z]D NQJ8^\

(476) GSZ`LXKHNR\

(477) J N)ÊLMGUKbNRea+PLXGmISYLMErD,I.\X^KbY+DIHD-D6tDeKbI.^LXGm^GS\

(478) Z KbY+D@E+GH\

(479) Er\

(480) GUKbNR\MJLMP NQJKbD,J8IHNQKWc.Z]\ V+D,P/zvDGHDe,\

(481) J+ISNRV+DGHDVn. . . >A@. +. . . -,/.102 -, 4EHGE 3VIC\J3C

(482). 365/E. .

(483) 8;,F 5< . .

(484) 4,/8 8. OSMX]NYFGAE. \

(485) GZ]LM#NRJ+dNRJ8^DGHDJ+e,D_zvDZ*a+ISKvYL2f

(486) DLIbLMZmE+PQDMn}xsY8NRIvIHLMZmE+PRD_NRI{LMPQzvL2c IvIHDPRDeKbDV. L e,e,\MGHV+NQJ+dKH\ LELMGUKbNQe,a+PRLMGwV+D,ISNRd

(487) JmzqY+NRe7Y]YLMIwKb\~p/DsKbLMMDJ.NRJKb\~LMee,\

(488) a+JK^\

(489) GNRJ8^DGUT X DJ+e,DXnwCDzqNQPRP^\4ea+IHIs\

(490) J KHY+DZ]\MISKse\

(491) Z]Zm\

(492) J.V8D,IHNQd

(493) J NRJ.zqY8NRe7YlL*GbLMJ8V+\

(494) Z IHLMZmE+PRD \X^yLkK7LMGSd

(495) DKqEr\

(496) E+a8PLXKHNR\

(497) J NQIK7LMXD,J-LXJ+VlKHY+D,J@NRI^\

(498) PQPR\z{D,V4Ta+EgV+a+GHNQJ+doIHD6f

(499) D,GHLMP:c

(500) D,LMGHIn vPQNRJ+NQe2LMP4ISKbLXKba+INRId

(501) DJ+D,GHLMPRP)ckLMISIHDIHIHDVgLXKE+GHDIHErD,eNQDV`f NRIHN)KbILMJ8V]f NQKbLMP+ISKbLXKba8I{e,LMJ prD*\

(502) p8IHD,GUf

(503) DV&NQJFe,\

(504) JKbNQJ#a+\

(505) a+I>KHNRZmDMn \

(506) GISKba8V8c NRJ+dgV+DZ]DJ#KHNL8§rKbY+D*KbLMGHdMDKEr\

(507) E+a8PLT KHNR\

(508) J]Z`L2coprDKHY+D>Er\

(509) E+a+PRLXKbNQ\

(510) Jm\M^:IHa8p SD,e6KbIqLMd

(511) DV.Zm\

(512) GHDqKbYLXJ ! PQNQf NRJ8d~NQJ.L~eD,GUK7LMNQJ .

(513) . GSD,d

(514) NQ\

(515) Jn:\

(516) G$p/DNRJ+d_IHDPRD,e6KbDV*IHa+p#SD,eKHIyZ*a+IUKyprDvLXPRNQfMDLXK$KbNRZmD \M^+KHY+D{NQJ+NQKHNLMPXf4NQIHN)K2n u^LMd

(517) DoNRIKHY+D]p+LMIHNQeoKHNRZmD6TIHe2LXPR D NRIKHY+DmLMd

(518) D]LXKNRJ+N)KbNLXP f NRISNQKzqY+NQe7YNRIV+N)tDGHDJ#K ^GS\

(519) Z \MJ+DkIHa+p#SD,eKKb\gLXJ+\MKbY8D, G #$z{Dm\MZ]N)K>KbY8DkIHa+ErD,GSIHe,GSNRE8K ^\

(520) GISNRZmE+PRNQe,N)KWc

(521) nxsY+NRI NQIsL*PRD6^KSTKbGHa8J+e2LXKHNR\

(522) J]e,\

(523) J8V+NQKHNR\

(524) J- © n >^KbDJ.KbY+DKHGHa+J8e2LXKHNR\

(525) J.e\

(526) J+V+N)KbNQ\

(527) J.NRI D| KbD,J8V+D,V pcmD6|4e,PQa+V+NQJ+dKHY+D>V8D,ZmD,JKbDV.IHa+p#SD,eKHIsLXKKbY8D>NRJ8NQKbNRLMP4f NQIHNQKprD,e,LMa+IHDNQKNRI V8N me,a+P)KKb\ Y+LfMDmL.GHD,E8GHD,ISD,JK7LKbNQfMDoIbLMZmE+PRD \M^V+D,ZmD,JKbDV&ISa+p SDeKbI #}NQJKbYLKe2LMISD KHY+DKbGSa+J+e,LXKbNQ\

(528) J.e,\MJ+V+NQKHNR\

(529) J`p/De,\

(530) ZmD,I ISa+p SDeKbIqYL2fMDKH\kp/DLMPRN)f

(531) DLMJ8V J8\

(532) J4TWV8D,ZmD,JKbDVlKH\]prDNRJ+ePRa+V8D,V n. 1 1 . HAL author manuscript. . > =. . 1 . . [/OSETVUM43VIC\J V3 IK] EO. p+ISD,GUfMLKbNR\MJ\M^yKHY+D E8GH\ e,D,ISIHDIZ`L2clprD~NQJV+NQIHe,GSDKHD \

(533) G_NRJ@e,\

(534) JKbNQJ#a+\

(535) a+I_KbNRZmDMnsxsY8D. inserm-00262112, version 1. Zm\

(536) IUK-e,\MZ]Zm\

(537) J ELKHKbDGHJ\Mô\Mp+IHDGSfXLXKbNQ\

(538) J NQJ ISKHa+V+NRDIF\

(539) J V+DZ]DJKbNL[NQI-LZmN)|4DV V8NRIHeGHD6KbD6Te,\

(540) JKHNRJ#a+\

(541) a+Ik\MJ+D NRJzqY+NQe7YKbY+D ePRNQJ+NRe,LMP{IUK7LXKHa+IkNRI \

(542) p+IHDGSfMD,V9LXKkV+NQIHe,GSDKHD f NQIHNQKKHNRZmD, I _§#zqY+NRPQD_KHY+DV+LXKbD\M^:V+D,LXKbY.e,LMJ`prD>GSDKHGHNRD6f

(543) DV.J+D2LXGHPQcoD|#T LXeKbP)c

(544) n CD_IHYLXPRPLMISIHa+ZmDqKbYLXKKHY+Dsf4NQIHN)KwKbNRZmD,ILXGHDqE+GHDIHErD,eNQDV§4KHY a8IKHYLXKELMGUK\M^ KHY+DZmD,e7YLMJ8NRIHZ PRD,LMV+NRJ8d Kb\kNQJ+e,\

(545) ZmE+PQDKbD>VLXK7L*e,LMJgp/DNQd

(546) J+\

(547) GSD,Vn = \

(548) ISKq\X^KbD,J KHY+D,GSD LXGHDLMPQIH\*ZmNRISIHNRJ8d*VLXKbL8yKbYLKsNRIsLkISa+p SD,e6K_IHY+\

(549) a8PRV YL2f

(550) DprD,DJ@ISD,D,J@LX K IHL2c

(551) §+p+a4K e\

(552) a+PQVJ+\MK~p/De2LMa8IHD \M^qGSDâ+IHLMP{\MG e7YLMJ8d

(553) D.\M^qLXV+GHDIHI,nFuWJ&KbYLXK e2LMISD`KbY8D`ZmNRIHISNRJ+d LK>GHLMJ+V+\

(554) Z LMISIHa+ZmE8KHNR\

(555) J@NRI_ a8D,ISKHNR\

(556) J+LMp+PRDXv^\

(557) GNRJ+IUK7LMJ+eD~V8D,ZmD,JKbDVFIHa+p SDeKHIZ`L2c GSDâ+ISD~Zm\

(558) GSD\M^KbDJlKHYLMJlJ+\

(559) J4TV+D,ZmD,JKHD,Vn. 3 & & & .

(560). 8:

(561) 5< . >A@. I 0_EHGAI

(562) 5/C6C6D. C&Dd

(563) NQfMDKHY+DPRNRXD,PQNRY+\ \4V^\MG$KHY+DNRPRPQJ+D,ISIUTV+D2LXKHYZ]\ V+D,P

(564) ^\MG$KHY+DKbGHa8J+e2LXKHNR\

(565) Je,\MJ+V+NQKHNR\

(566) J LMJ+VlLMISIHa+ZmNRJ+doZmNRISIHNRJ8dkLXKqGbLXJ+V+\

(567) Z VLXK7L #8KbY+DPQNRXD,PRNQY+\ \4V]NRIsd

(568) N)f

(569) D,J ^\

(570) G \MJ+DsIHa+p#SD,eK,§4V8GH\

(571) E+E8NRJ+dKHY+D :IHa+p8IHe,GSNRE8Kw^\MGyIHNQZ]E+PQNReNQKWc %LXPRP4KHY+Ds#aLMJKbN)KbNQD,IwJLMZmD,P)c § 2. § / § § ^ § §sZ]L2c9V8D,ErD,J+VO\

(572) J #KbY+D-dMPR\

(573) pLXPsPRNRXD,PQNRY+\ \4V^\

(574) G § \Mp+IHDGSfXLXKbNQ\

(575) J.\M^ L~IbLMZmE+PRD_\M ^ -NQJ+V+DE/DJ+V+D,JKqISa+p SD,e6KbIzqNQPRPp/DKbY+DE8GH\ V+a+eKv\M^:KbY8D NQJ+V+N)f4NQV+aLMP PRNQMDPRNRY8\4\ V+I,n p+ISD,GSfXLXKHNR\

(576) J8I\M^ LXGHD*K7LXMD,J LX K FLMJ8V KHY+D f NQKbLMP ISK7LKba+INQI>\

(577) p8IHD,GUf

(578) DV&a+JKHNR P #Y+DGH D @NQI>KbY8D*PLMIUKf NQIHNQKKbNQZ]D \X^LMJ-LXPRNQfMDIHa+p SDeK,n>:DKa+Ie2LMPQP ^ KbY+D^\

(579) PRPQ\zTWa+EgKbNQZ]DKHYLXKNR! I ^ ZmNRJ ^ 6§ zqY8D,GHD ^ NQIKbY+DKHNRZmD\M^V+D2LXKHY #+z{D~\

(580) p8IHD,GUf

(581) " D ^ LMJ+# V ^%$& #n xsY+DkPQNRXD,PRNQY+\ \4Vge2LXJFp/D*Zm\

(582) IUKJLXKHa+GbLXPRPQc zqGSNQKSKbD,JFNQJKbDGHZ \M^pr\MKbYKHGbLMJ8IHNQKHNR\

(583) J. 1

(584)

(585) 1. . . . . . . . . !. 1 . & & & . #.

(586)

(587)

(588) % .

(589) 1 2 ^ ^8 2 ^ ^8 A$#.

(590). NQJKbD,J8IHNQKHNRDI LXJ+VkKbGbLXJ+IHN)KbNR\MJkE+GH\

(591) p+LMp+NRPQNQKHNRD,I 6n u^4KbY+DIHa8p SD,e6KwISKbLMGSKHINQJIUK7LXKHD UY+D2LMP)KbY 8§XYLXIJ+D6f

(592) DG}prD,D,J~\

(593) p+ISD,GSfMD,VkNQJKHY+D SNRPQPRJ+DIHI IUK7LXKHDLMJ+VgzLMIqPRLMISKqISD,D,JLXKsf NRISNQK LXKsKbNQZ]D {KbY+DPRNQMDPRNRY8\4\ V.NRI HAL author manuscript. . )N ^wKbY+DkISa+p SDeK~YLMIprD,D,J\

(594) p8IHD,GUf

(595) DVNRJ-KHY+DkNRPQPRJ+DIHIISK7LKbD*^\

(596) G>KHY+D*GSISKKbNQZ]D*LXK KHY+D,JgKbY8DPQNRXD,PRNQY+\ \4V.NQI, . . 1

(597) ^8 ^ & . inserm-00262112, version 1. x YLK>KbY8NRI_NRIqKbY+D~PRNRXD,PQNRY+\ \4V Y+LMIprD,DJ-GHNQd

(598) \

(599) GS\

(600) a+IHP)c E+GS\0fMD,VFNQJ %nsxsY+D~KHGbLMJ4T s ISNQKHNR\

(601) J E+GS\

(602) pLMp8NRPRN)KbNQD,ILXGHDPRNQJ+MDVlKH\kKbY+DKbGHLMJ+ISNQKbNQ\

(603) J NRJKHD,J+ISNQKbNQD,Ispc.KHY+D^\

(604) GHZ*a8PLMI.

(605)

(606) / 0

(607) / 0 / 0

(608)

(609)

(610)

(611)

(612)

(613) @NQIKbY+Dea+Z*a+PRLXKbN)f

(614) DNRJKHD,J+ISNQKWc prDKWz{D,DJ B M /IA]NI M4V3 IAC_J C 36/ 5 E GAI _0 EHGAI

(615) /5 C6C6D . .

(616). . . .

(617). zqY8D,GHD. >=. . .

(618). n. LMJ8I. . PRLMIHISNRe,LMPsNRJ8^DGHDJ+e,D@GHD,#a+NQGHDImKHY+DZ]L|4NRZmNRh,LXKbNQ\

(619) J\M^KbY+DlPRNQMD,PQNRY+\ \ Vn\

(620) GoELXGbLT v ZmDKHGHNQelZm\ V+D,PsKbY8D@PQNRMDPRNQY+\4\ Ve2LXJprDZ]L|4NRZmNRh,DVzqNQKbY8\

(621) a8K]E+GH\

(622) p8PRD,Z a+IHNQJ+d&^\

(623) G NQJ+ISKbLMJ+eDL GS\

(624) p+a+IUK D6zsKb\

(625) J T A LME+Y+IS\

(626) JgLMPRdM\

(627) GHN)KbY+Zln ; \

(628) ZmD_z{\

(629) GHmYLMI{p/DD,J V+\MJ+D^\

(630) G J8\

(631) J4TWGSD,IUKbGHNQeKHD,V J+\

(632) J4TELMGbLXZ]D6KbGHNQekNRJ8^DGHDJ+e,Dmpc GUc V+Z`LX J T ' %§:zqY+\@E8GH\

(633) Er\

(634) IHDV = LMPRdMGHNQKHY+Zln ? J@LKHKbGHLMeKHNQfMDLME+E+GS\LMe7YgNRIKH\ma8IHDL*IHZm\4\XKbY J+\

(635) J TWELMGHLMZmDKbGSNRe LXJ LXE+E+GH\

(636) LMe7Y9ISa+e7Y9KHYLXKmLMe7Y8NRDfMD,V9p#cE/DJLMPRNQh,DV PQNRXD,PRNQY+\ \4P V (T "! %nuWJ KbY8DlISD,ZmN)T E+LMGbLMZmDKHGHNQee,LMIHD>zqY8D,GHD>\

(637) J+D>p+LMIHDPRNRJ8Dâ+J+e6KbNQ\

(638) J.NRID,IUKbNQZ`LXKHD,V`^\MG{D,LMe7Y.KbGHLMJ+IHN)KbNQ\

(639) J§ KHY+DE/DJLMPQNRh,DVgPRNRXD,PQNRY+\ \4V]NRI. 7. & &

(640) .

(641)

(642) zqY8D,GHD NQIKbY8D*PR\

(643) dMPRNRXD,PQNRY+\ \4Vt§ qNRI_KbY+D*Z]LXKHGHN)|l\X^wpLMISD,PRNQJ+D Y+LMh2LMGSV-â+J+e6KbNR\MJ+I,§ NQIKHY+DLMGSGbL2co\M^:fMD,eKH\

(644) GHIv\M^:GHDd

(645) GHD& IHISNR\

(646) J.E+LMGbLMZmDKHD,GSI

(647) § GSD,E+GSD,ISD,JKbIKHY+D>VLK7L8n xsY8DErD,JLMP)KWcKbDGHZ D6|4ePRa+V+DI]KHYLXKmV+NRISe,GSDKbD@\

(648) Goa+J+ISZ]\ \MKbY â+J+e6KbNQ\

(649) J+ImZ`L|4NQZ]NQh,D . . . . . . . . . .

(650) . & 6n xsY+DqIH\MPRa8KHNR\

(651) J*\X^rKHY+DsErD,JLMPQNRhD,VkPRNQMDPRNRY8\4\ V NQIwLME+E+GS\2|8NQZ`LKbD,Vka8IHNRJ8d L~pLMIHNQIv\M^$ISE+PRNQJ+D,IvLMJ+V.e,LMJgLMPQIH\ prDe\

(652) Z]E8a8KbDV.a+IHNQJ+dkL GS\

(653) p+a+IUK D6zsKb\

(654) J T A LME+Y+IS\

(655) J . . HAL author manuscript inserm-00262112, version 1. L PRd

(656) \

(657) GSNQKHY+Z@n xsY8D.e,\

(658) ZmE+a8KbLXKbNQ\

(659) J&LMGHD]IHNRZmE+PQD,GzqY+D,JKHY+D,GSD.NRI~J+\KbNQZ]DTWV+DE/DJ+V+DJ#K X fXLMGSNLMp8PRD,IkprD,e,LMa+ISD@N)KoNRIkEr\

(660) IHISNRp+PQDgKH\GHD,E8GHD,ISD,JK`KHY+D KbGHLMJ+IHN)KbNQ\

(661) J NRJKbDJ+IHN)KbNRDIk\

(662) J9L p+LMIHNQI\M^ TIHE+PQNRJ+DILMJ+V-KHY+Dke,a8Z*a+PLKbNQfMD NQJ#KHD,J+ISNQKHNRD,I\

(663) JL.pLMISD*\MûTWISE+PRNQJ+D,I_zqNQKHY KHY+DIbLMZmDe,\ D meNRD,JKHI,§KbY#a+IL2f

(664) \

(665) NQV+NRJ+dkIS\

(666) ZmDJ#a+ZmD,GSNRe,LMPNRJKHD,d

(667) GHLMPRI ! %n ? e,\

(668) ZmZ]\MJÈ+GS\

(669) p+PRDZ \M^ LMPQPKHY+D>ISZ]\ \MKHY+NRJ+dZmDKbY8\4V+I{NRIKb\*e7Y8\4\

(670) ISD>KbY8D>V+Dd

(671) GHDD \XÎHZm\ \MKbY+J8D,IHI\M^KHY+DmD,ISKHNRZ]LXKb\MGHI,n.vGH\

(672) ISIUTfMLXPRNRV+LXKbNQ\

(673) JFYLMIp/DD,J KbY+D]Z]\

(674) IUK\M^KbDJ a8IHD,VZmDKHY+\4Vtn uWJLMJ[NQPRPRJ8D,IHI TWV+D,LXKbY9Z]\ V+DP§s\

(675) J+DYLMI`KH\Z`L0|8NQZ]NQh,D KbY8D-e,GS\

(676) IHI T fXLMPQNRVLKbNR\MJe,GSNQKbDGHNQ\

(677) J *\

(678) J KbY+DgKbY+GSD,DlIHZm\4\XKbY+NQJ+dELMGbLXZ]D6KbD,GS I # KHY+NRIsNQIsV+N mea+PQKqp+a4KZ]L2c.prD V+\

(679) J+ DLME+ E8GH\2|4NRZ]LXKbDPQc]p#cgdMGHNRV ZmDKHY+\ V+I,n xsY+DGHDYLMIsprD,DJ@GSD,PLKbNQfMD,P)c]^D6z z{\

(680) GH#I_\

(681) J KbY+DLXISc Z]E4Kb\MKHNReE+GS\

(682) E/DGSKHNRD,Is\X^ KHY+NRI LXE+E+GH\

(683) LMe7Y*IS\

(684) Z]DmGHDIHa+P)KbI~\

(685) J&KHY+D.LMIUc Z]E8KH\MKbNQeoE+GH\

(686) ErD,GUKbNQD,I\M^KbY8D]ErD,JLXPRNRhD,V&PRNRXD6T PQNRY+\ \ VYL2f

(687) DkprD,DJd

(688) NQfMD,JFp c a yp+a4KKb\ \

(689) a8G#J+\zqPRD,V8d

(690) DM§:J+\XKbY+NQJ+d.YLMIprD,DJ E8a+p+PRNQIHY+DV-\

(691) J-KHY+D*E+GS\

(692) E/DGSKHNRD,I\M^wKbY8DkLME+E+GS\LMe7YFe\

(693) Z*p+NQJ+NRJ+dmErD,JLMPQNRhD,V-PQNRMDPRNQY+\4\ V LXJ+V@eGH\

(694) ISIUTfMLXPRNRV+LXKbNQ\

(695) Jn _\0z{DfMD,GIHDfMD,GHLMPISNRZ*a8PLXKHNR\

(696) J.IUKba+V8NRD,% I ! § (+§ ! § © :Y+LfMD ISY+\zqJd

(697) \ \ V D,ZmE+NRGSNRe2LXPtE+GS\

(698) E/DGSKHNRD,Is\X^}KbY8D,IHDDISKbNQZ`LKb\

(699) GSI,n. '. . . . *.

(700) ?>A@. ,F8

(701) . 8 0)

(702). -,. 5

(703) . 8:

(704) . / 5 E M RFID3O V3 R/D$. xsY8DLME+E+PQNRe2LKbNR\MJ`NRIvpLMIHDV@\MJ.KbY+DLM#a+NRVgGHDIHD,LMGHe7YlE+GH\Md

(705) GbLMZmZmD ©R %§+L*E+GS\

(706) IHErD,eT KHNQfMDle\

(707) Y+\

(708) GUKoISKHa+V8c \M^>Z]DJ#KbLMPsLMJ8V9E+Yc IHNQe2LMP_LMdMNRJ+d-KHYLXKoDfXLMPQaLXKHD,IoIH\ e,NRLMPD,Jf N)T GS\

(709) J+ZmD,JK>LMJ+VY8D2LMP)KbYlISK7LKba+InsxsY+D~KbLMGHd

(710) D6K_E/\

(711) E8a+PLXKHNR\

(712) Jge\

(713) J+IHNQISKHI\M^yIHa+p SDeKHILMd

(714) DV ! c

(715) D2LXGHIlLMJ+V\

(716) PQV+D,G PQNQf NRJ+dLXKgY+\

(717) ZmD-NQJOIH\

(718) a8KHYzvDISKbDGHJ GHLMJ+e,DXn xsY+DpLXIHD,PQNRJ+D fXLMGSNLMp8PRD,I{GHDd

(719) NRIUKbD,GSD,VgNRJ8e,PRa8V+D,VgIH\ e,NQ\XTWV8D,Zm\

(720) d

(721) GbLXE+Y+NReq^LMe6Kb\

(722) GSI,§+ZmD,V+NQe2LMP/Y+NRIUKb\

(723) GUc LMJ8V E8ISc e7Y+\

(724) ZmDKHGHNRe-KHD,IUKbI, n NRLMd

(725) J+\MIHNRI]\M^V+D,ZmD,JKHNLzLXI Z`LMV8DLMe,e\

(726) GHV+NQJ+dKb\ LKWz{\ IUK7LMdMDkE+GH\ e,DV+a+GHDXKbY+DkE8ISc e7Y+\

(727) PQ\

(728) d

(729) NRIUKzqY+\ PRPQD,V-KHY+Do a8D,ISKHNR\

(730) J8JLMNRGSD*IHeGHDD,J+DV&KbY8D ISa+p SDeKbI_LMI{E/\MIHIHNQp+PQcmV+DZ]DJKbD,VlLMee,\

(731) GSV+NRJ8d~Kb \ ;8= TWuSuHuT A \

(732) G{J+\M K #8IHa8p SD,e6KbIqe,PRLMIUT ISNQDV[LMImEr\

(733) IHN)KbNQfMD zvDGHDPRLXKbDGoIHD,DJOpc L&J+Da+GH\

(734) PQ\

(735) d

(736) NQISKkzqY+\&e,\

(737) J8+GHZmD,V \

(738) GoJ+\MK KHY+DmV+NLMdMJ+\

(739) IHNQI\M^V+DZ]DJKbNL@LMJ+V&Z`LMV8D]LlZ]\MGHDoIHErD,eNQemV+NLXd

(740) J+\

(741) ISNRI,§LMISIHD,ISIHNQJ+d-NRJ E+LMGSKHNRe,a8PLMGKbY+D u ; T ? A ? eGHNQKHD,GSNLl^\MG ? PQh,Y+DNRZmD,Gi¦I~V+NRISD2LMISDMn ; a+p#SD,eKHI z{D,GSDGHD6TDfXLMPQaLXKbDV § ' § ! LMJ+V LMJ+V c

(742) D,LMGHI_LX^KHD,GvKHY+DNRJ8NQKbNRLMPf NRIHN)K2nwwGSDfXLMPRDJK e,LMIHDIz{D,GSD GHDZ]\fMD,V^GS\

(743) Z KbY+DIbLXZ]E+PQDp/De2LMa+ISD N)K_zvLMI_Z]\MGHDV+N me,a8PQKsKb\]YL2f

(744) D L GSD,E+GSD,ISD,JK7LXKHNQfMDIHLMZ]E8PRD\M^/LEr\

(745) E+a+PRLXKbNQ\

(746) J NQJ+e,PQa+V+NRJ8dV+D,ZmD,JKHD,VmE/D\

(747) E+PRDXnyxsY+DGHD^\MGHDM§. . . . @.

(748) HK Y+NRIqE+GS\4V8a+e,DVFLmPQD^KUTKbGSa+J+e,LXKbNQ\

(749) JgE+GH\

(750) p8PRD,ZlnvxsY8D~IHLMZ]E8PRDe,\

(751) J8IHNRIUKbDV\M^ ' ) ! IHa+p T SDeKHI,n a+GSNRJ+doKbY+D c

(752) D,LMGHI\M^y^\

(753) PQPR\zTWa+Et§V( ' kNRJ+eNRV+DJK>e,LMIHDI>\M^}V+D,ZmD,JKbNRLoz{D,GSD \Mp+IHDGSf

(754) DV \M^tzqY8\

(755) Z V+NRDV # 0© 2IHa8p SD,e6KbIvz{D,GSD>\

(756) p+ISD,GUf

(757) D,V NQJkKbY+D_Y+D2LXPQKbYcoIUK7LXKHD LKKHY+D>PRLMISKf NRISNQKprD^\

(758) GSDV8D2LXKHY V8a+DKH\KHY+DNQJKbD,GUfXLMPe,D,J8IH\

(759) GSNRJ+d~ELMGSK\M^/KbY+DZ Z`L2c Y+LfMDgV+DfMD,PR\ME/DV9V+DZ]DJKbNLFprD^\

(760) GSD V+D2LKbYzqNQKHY+\

(761) a8KkprD,NQJ+d\

(762) p+ISD,GSfMD,V9V+D,ZmD,JKbDV 6n ? J-LMJ+LMPQc IHNQIqYLMVlp/DD,JZ]LMV+Da+ISNRJ+d`LoKHY+GHDD6TISK7LKbDE+GH\

(763) dMGHD,ISIHN)f

(764) D Zm\ V+D,Pt^\MGqKHGSc NRJ8d KH\.D,IUKbNQZ`LXKHD~KHY+D*Zm\

(765) GSKbLMPRN)KWcgGbLXKHD NRJV+D,ZmD,JKbDVIHa+p SDeKHI ©

(766) © %n _D,GHD*z{D*a+ISD,VFKbY8D Zm\

(767) GSDLXVLME8KHD,V`NQPRPQJ+D,ISIUTWV8D2LXKHYmZm\ V+D,P%§

(768) GHIUKva+ISNRJ+dKbY8DIUK7LXKHNR\

(769) JLXGSc*fMD,GHISNR\

(770) Jt§ KHY+D,J]NRJ4T ePRa+V8NRJ+d]e2LMPQD,J+VLXG>KbNQZ]DXnC&D*a+IHDVFKbY+D*ErD,J+LMPRNQh,D,VPRNRXD,PQNRY+\ \4V@LME+E8GH\LMe7YFV8D,E+NQeKbDV NQJ@ISD,e6KbNR\MJ (+n © LXJ+V@a8IHNRJ8dè,a8p+NReIHE8PRNRJ8D,IqzqNQKbY k J8\MKbI_^\

(771) GsKbY+D~LME+E+GS\2|8NQZ`LKbNR\MJ \M^ D,LMe7YkNRJKHD,J+ISNQKWcâ+J+eKHNR\

(772) ` J #MKbY+D{ELMGHLMZ]D6KbDGHI}z{D,GSDD,IUKbNRZ]LXKHD,V*a+ISNRJ+dL>GH\

(773) p8a+ISKf

(774) D,GSIHNQ\

(775) J \X^KHY+D DzsKH\

(776) J4T A LME8Y+IH\