Suivi prospectif d’une cohorte de femmes enceintes chroniquement infectées par le virus de l’hépatite B (VHB) et de leurs enfants en RDP Laos

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(1)Suivi prospectif d’une cohorte de femmes enceintes chroniquement infectées par le virus de l’hépatite B (VHB) et de leurs enfants en RDP Laos Vatthanaphone Latthaphasavang. To cite this version: Vatthanaphone Latthaphasavang. Suivi prospectif d’une cohorte de femmes enceintes chroniquement infectées par le virus de l’hépatite B (VHB) et de leurs enfants en RDP Laos. Virologie. Université de Lyon, 2018. Français. �NNT : 2018LYSE1336�. �tel-02096567�. HAL Id: tel-02096567 https://tel.archives-ouvertes.fr/tel-02096567 Submitted on 11 Apr 2019. 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) N°d’ordre NNT :. 2018LYSE12336. THESE de DOCTORAT DE L’UNIVERSITE DE LYON opérée au sein de. l’Université Claude Bernard Lyon 1 Ecole Doctorale N°341 Evolution, Ecosystème, Microbiologie, Modélisation (E2M2) Spécialité de doctorat : Epidémiologie clinique Soutenue publiquement le 19/12/2018, par :. Vatthanaphone LATTHAPHASAVANG. Suivi prospectif d’une cohorte de femmes enceintes chroniquement infectées par le virus de l’hépatite B (VHB) et de leurs enfants en RDP Lao 3C/;A938B?E1<:=<@J23 . 1)# (.+@ADAHH=+0 +#0FAN=JKALWD9M<==JF9J<'QGF "''4FF=?=F;=)9LAGF9D=<=.9FLW+M:DAIM=-9HHGJLJA;= .*")$+@ADAHH=+0 +#0FAN=JKALW+9JAK=K;9JL=K-9HHGJL=MJ (/# -*).GH@A=+0 +#0FAN=JKALW+9JAKA<=JGL P9EAF9LJA;= /- +*@JAKLA9F+JG>=KK=MJSE=JAL=0FAN=JKALWD9M<==JF9J<'QGF P9EAF9L=MJ 1) + -- +@ADAHH=+0 +#0FAN=JKALW<=(GFLH=DDA=J P9EAF9L=MJ )4+9MD+0 +#0FAN=JKALW+9JAK G <AJ=;L=MJ<=L@XK= %*0-$)"GFR9?M=@9J?W<=J=;@=J;@=K$FKLALML<=J=;@=J;@=HGMJD= <WN=DGHH=E=FL$-G <AJ=;L=MJ<=L@XK=. .

(3) UNIVERSITE CLAUDE BERNARD - LYON 1 Président de l’Université. M. le Professeur Frédéric FLEURY. Président du Conseil Académique. M. le Professeur Hamda BEN HADID. Vice-président du Conseil d’Administration. M. le Professeur Didier REVEL. Vice-président du Conseil Formation et Vie Universitaire. M. le Professeur Philippe CHEVALIER. Vice-président de la Commission Recherche. M. Fabrice VALLÉE. Directeur Général des Services. M. Alain HELLEU. COMPOSANTES SANTE Faculté de Médecine Lyon Est – Claude Bernard. Directeur : M. le Professeur J. ETIENNE. Faculté de Médecine et de Maïeutique Lyon Sud – Charles Mérieux. Directeur : Mme la Professeure C. BURILLON. Faculté d’Odontologie Institut des Sciences Pharmaceutiques et Biologiques Institut des Sciences et Techniques de la Réadaptation Département de formation et Centre de Recherche en Biologie Humaine. Directeur : M. le Professeur D. BOURGEOIS Directeur : Mme la Professeure C. VINCIGUERRA Directeur : M. le Professeur Y. MATILLON Directeur : Mme la Professeure A-M. SCHOTT. COMPOSANTES ET DEPARTEMENTS DE SCIENCES ET TECHNOLOGIE Faculté des Sciences et Technologies. Directeur : M. F. DE MARCHI. Département Biologie. Directeur : M. le Professeur F. THEVENARD. Département Chimie Biochimie. Directeur : Mme C. FELIX. Département GEP. Directeur : M. Hassan HAMMOURI. Département Informatique. Directeur : M. le Professeur S. AKKOUCHE. Département Mathématiques. Directeur : M. le Professeur G. TOMANOV. Département Mécanique. Directeur : M. le Professeur H. BEN HADID. Département Physique. Directeur : M. le Professeur J-C PLENET. UFR Sciences et Techniques des Activités Physiques et Sportives Directeur : M. Y.VANPOULLE Observatoire des Sciences de l’Univers de Lyon. Directeur : M. B. GUIDERDONI. Polytech Lyon. Directeur : M. le Professeur E.PERRIN. Ecole Supérieure de Chimie Physique Electronique. Directeur : M. G. PIGNAULT. Institut Universitaire de Technologie de Lyon 1. Directeur : M. le Professeur C. VITON. Ecole Supérieure du Professorat et de l’Education. Directeur : M. le Professeur A. MOUGNIOTTE. Institut de Science Financière et d'Assurances. Directeur : M. N. LEBOISNE. . .

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(27)

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(32) T

(33) =L=KLEAFAE=KADoAF>=;LAGFKMJNA=FLTDo9?=9<MDL=EGAFK<=6 7 'oAF>=;LAGF;@JGFAIM= H9J D= 1# =PHGK= =FKMAL= D=K E9D9<=K T MF JAKIM= AEHGJL9FL <= <W;XK H9J ;AJJ@GK= =L ;9F;=J@WH9LAIM=TDoU?=9<MDL= =KRGF=K<=@9ML==F<WEA;ALWKGFL<GF;H9JLA;MDAXJ=E=FL LGM;@W=KH9JD=K;GEHDA;9LAGFK<=Do@WH9LAL=;@JGFAIM= =Fo=KLIM=JW;=EE=FLIM=Do*J?9FAK9LAGF(GF<A9D=<=D9.9FLW*(.9J=EAKTDnGJ<J= <M BGMJ <=K HJAGJALWK <= K9FLW HM:DAIM= D9 DMLL= ;GFLJ= D=K @WH9LAL=K NAJ9D=K =F NM= <= DoWDAEAF9LAGF<=D9LJ9FKEAKKAGF=L<=D=MJK;GEHDA;9LAGFK<oA;A

(34)

(35) '9HJWN=FLAGF<=;=K ;GEHDA;9LAGFKH9KK=H9JD=<WHAKL9?=<=KH=JKGFF=KAF>=;LW=KD=MJWN9DM9LAGFD=MJKMANA=L MFLJ9AL=E=FLT NA= T H9JLAJ <oMF ;=JL9AFKL9<=<oWNGDMLAGF<= D9E9D9<A= =<WHAKL9?==L ;=LL=HJAK==F;@9J?=F=KGFLH9KEAK=FHD9;=<9FKDoAEE=FK=E9BGJALW<=KH9QKT>9A:D=K =LEGQ=FKJ=N=FMKE9D?JWDo=PAKL=F;=<=HDMKA=MJKEW<A;9E=FLK9FLANAJ9MP=>>A;9;=KIMA AF@A:=FLD9JWHDA;9LAGF<M1# F ;= IMA ;GF;=JF= DoWDAEAF9LAGF <= D9 LJ9FKEAKKAGF <M 1# MF N9;;AF LJXK =>>A;9;= =L <AKHGFA:D=H9JLGML<9FKD=EGF<=TMFHJAPEG<WJW=PAKL=<=HMAKD9>AF<=K9FFW=K

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(37) $D =KL <GF; =KK=FLA=D <= HJWN=FAJ DoAF>=;LAGF H9J Do@WH9LAL= H9JLA;MDAXJ=E=FL ;@=R D=K FGMN=9M FWK=LD=K=F>9FLK=FWLM<A9FL=L=F9EWDAGJ9FLD=KEWL@G<=K<=HJWN=FLAGFHMAK =FD=KE=LL9FL=FkMNJ=<9FKD=KKQKLXE=K<=K9FLWHM:DAIM= M'9GKD=HJG:DXE=<=D9LJ9FKEAKKAGFHWJAF9L9D=9WLWKGMD=NW<=HMAKHDMKA=MJK9FFW=K (GF LJ9N9AD <= L@XK= 9 =M HGMJ G:B=;LA> <= <W;JAJ= D9 KALM9LAGF <9FK <=MP @]HAL9MP <= D9 ;9HAL9D=9>AF<=<W;=D=J<oWN=FLM=DKHJG:DXE=KIMAK=HGK=J9A=FLDGJK<=D9EAK==FkMNJ= <=KJ=;GEE9F<9LAGFK<=Do*(. '=LJ9N9AD=KL<ANAKW=F;@9HALJ=K • '=HJ=EA=J;@9HALJ==KLMFJ9HH=D<=K;GFF9AKK9F;=K9;LM=DD=KKMJDo@WH9LAL= • '=K=;GF<;@9HALJ==KL;GFK9;JWTD9KALM9LAGF<=Do@WH9LAL=;@JGFAIM=9M'9GK=LT K9HJAK==F;@9J?= • '= LJGAKAXE= ;@9HALJ= HJWK=FL= D=K JWKMDL9LK <= DoWLM<= <= ;G@GJL= HJGKH=;LAN= <= >=EE=K=F;=AFL=KAF>=;LW=K;@JGFAIM=E=FLH9JD=1#=L<=D=MJK=F>9FLK9MP'9GK IMA9WLWEAK==FHD9;=<9FKD=;9<J=<=;=LJ9N9AD<=L@XK= • '= IM9LJAXE= ;@9HALJ= HJGHGK= <=K ;GF;DMKAGFK T ;= LJ9N9AD =L D=K H=JKH=;LAN=K GMN=JL=KTD9KMAL=<=;=LJ9N9AD • '=;AFIMAXE=;@9HALJ=HJWK=FL=D=K;GEEMFA;9LAGFKGJ9D=K=F;GF?JXKJW9DAKW=K9M ;GMJK<=;=LJ9N9AD<=L@XK= . . . .

(38) 6/=7A?3'/==39@B?9T6J=/A7A3 9FK ;= ;@9HALJ= FGMK JWKMEGFK <=K AF>GJE9LAGFK AEHGJL9FL=K FW;=KK9AJ=K T D9 ;GEHJW@=FKAGF <= ;=LL= L@XK= FGL9EE=FL D9 <W>AFALAGF <= Do@WH9LAL= MF= <=K;JAHLAGF KM;;AF;L=<MNAJMK=F;9MK=D=KEW;9FAKE=K<=DoAF>=;LAGFD=KEWL@G<=K<=<A9?FGKLA;<= DoAF>=;LAGFMF=<=K;JAHLAGFKM;;AF;L=<=D9E9D9<A=@WH9LAIM=9KKG;AW=TDoAF>=;LAGFH9JD= 1#=LKGFLJ9AL=E=FL . J47;7A7<;239T6J=/A7A3 'o@WH9LAL==KLMF=AF>=;LAGFNAJ9D=;9MKW=H9JD=1#IMAAF>=;L=D=K@WH9LG;QL=K DD=H=ML HJ=F<J=MF=>GJE=9A?MZGM;@JGFAIM= '=K;GEHDA;9LAGFK<=DoAF>=;LAGF;@JGFAIM=9;IMAK= <9FK Do=F>9F;= 9HH9J9AKK=FL @9:ALM=DD=E=FL 9HJXK

(39)

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(46) <= KMJ>9;= #K GM HJGLWAF= #K? '= ?WFGE= =KL >GJEW <o) ;AJ;MD9AJ=

(47)

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(53) 9;A<=K9EAFWK99IMABGM=D=J]D=AEHGJL9FL <9FK D=K 9;LANALWK KMAN9FL +GDQEWJ9K= -) <WH=F<9FL= J=N=JK= LJ9FK;JAHL9K= +GDQEWJ9K=) <WH=F<9FL=JWHDA;9LAGF=L-)9K=#67 .

(54) !/;A75K;31 '?#; =KL MF= HJGLWAF= IMA ;GEHGK= <o=FNAJGF <= T 99 o=KL D9 HJGLWAF= KLJM;LMJ9D= <= D9 ;9HKA<= $?( 9FLA #; KGFL D=K HJ=EA=JK E9JIM=MJK <AF>=;LAGF 9M 1# E9AK;=K9FLA;GJHKNGFL<AEAFM=JJ9HA<=E=FL<9FKD=L=EHKKGMKD=K=MAD<=<WL=;LAGF '=K 9FLA;GJHK<=LQH=$?(9FLA #;H=MN=FLJW9HH9J9ALJ=DGJK<=JW9;LAN9LAGFNAJ9D= 0F=JWHGFK= EWEGAJ=9HH9J9[LEW<AW=H9JD=K9FLA;GJHK<=LQH=$?"=LH=JKAKL=Tt NA=IM=DAF>=;LAGF KGAL9A?MZGM;@JGFAIM= '9HJWK=F;=<=K9FLA;GJHK$?" 9FLA#;=KLD=KA?F=<MF=AF>=;LAGF 9A?MZ =F ;GMJK ;@JGFAIM= GM <MF= AF>=;LAGF 9F;A=FF= =L JWKGDM= 6 7 ;o=KL <GF; MF E9JIM=MJ<=J=F;GFLJ=9FLWJA=MJ=9N=;D=NAJMK<=Do@WH9LAL= . !/;A75K;3353 '9FLA?XF=#==KLKQFL@WLAKWu =FL9FLIM=HJG HJGLWAF=<=C99N=;=F) L=JEAF9DD=K 99KMHHDWE=FL9AJ=K;G<=KH9JD9JW?AGF+JW o=KLMF=HJGLWAF=FGFKLJM;LMJ9D=IMA=KL K=;JWLW=<9FKD=KWJME<=KH9LA=FLKAF>=;LWK '9HJWK=F;=<=Do?#==KLMFE9JIM=MJLJXK MLAD=IMAHGMJJ9AF<AIM=JMF=JWHDA;9LAGFNAJ9D=9;LAN==LTDWL9:DAKK=E=FL<=D9;@JGFA;ALW67 '?#==KLLJXKAEEMFG?XF= '9KWJG;GFN=JKAGF9FLA #=E9JIM=D9>AF<=D9JWHDA;9LAGF NAJ9D= =L HGMJJ9AL 9FFGF;=J D= <W:ML <= D9 JWKGDMLAGF <= DAF>=;LAGF F>AF <=K KGM;@=K <= 1#?#= H=MN=FLWE=J?=JKMAL=T<=KEML9LAGFK<9FKD9JW?AGF+JW '=KKGM;@=K ?#= KGFLE9AFL=F9FL<=N=FM=KD9>GJE=E9BGJAL9AJ=<=KAF>=;LAGFK;@JGFAIM=K#1 <9FKD=EGF<=6

(55) 7. !/;A75K;3@5@ 'o?#K ;GFLA=FL =FNAJGF 99 ;o=KL D9 HJGLWAF= IMA ;GFKLALM= D9 H9JLA= E9B=MJ= <= Do=FN=DGHH=NAJ9D= '9;GFF9AKK9F;=<=K9KLJM;LMJ==P9;L=F=KLH9K=F;GJ=;D9AJ= 'o?#K =KLLJXKAEEMFG?XF==LD9HJWK=F;=<=KE9JIM=MJKKWJGDG?AIM=K;9FLA #KAF<AIM=MF= HJGL=;LAGF F9LMJ=DD= GM ;=DD= <oMF= H=JKGFF= AEEMFAKW= ;GFLJ= DoAF>=;LAGF 1# H9J D9 N9;;AF9LAGF '9H9JLA=<M<WL=JEAF9FLn9oIMAK=LJGMN=<9FKD9HJGLWAF=<=KMJ>9;==KLMF= RGF=AEHGJL9FL=IMAH=MLE=LLJ==F<W>9MLD9J=;GFF9AKK9F;=<=Do?#KH9JD=K9FLA;GJHK . .

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(90) 7 . . .

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(92) Do9FLA;GJHK9FLA #;=KL<=;D9KK=$?($?(9FLA #;TDoAFN=JK=MF=@WH9LAL=;@JGFAIM= 9;LAN= K= LJ9<MAL ?WFWJ9D=E=FL H9J MF= 9M?E=FL9LAGF =P;DMKAN= <=K 9FLA #; <= LQH= ?9EE9$?"9FLA #; +MAK9HH9J9[LDo9FLA;GJHK9FLA #=IMAH=JE=L@9:ALM=DD=E=FL;@=R Do9<MDL=JW;=EE=FLAF>=;LWD9;D9AJ9F;=<=Do9FLA?XF=#= =H9KK9?=<=DoWL9L<=HGJL=MJ <o9FLA?XF=T;=DMA<=HGJL=MJ<o9FLA;GJHKKA?F=D9KWJG;GFN=JKAGF '9KWJG;GFN=JKAGF#= =KLD=KA?F=IM=D9JWHDA;9LAGFNAJ9D=<AEAFM=9MLJ=E=FL<ALIM=D=NAJMKK=J=HJG<MAL9N=; EGAFK<=NA?M=MJ '9KWJG;GFN=JKAGF#KKo=FKMAL@9:ALM=DD=E=FL!A?MJ= HJXK D9 <AKH9JALAGF <= Do9FLA?XF= #K =L Do9HH9JALAGF <= Do9FLA;GJHK 9FLA #K ;= <=JFA=J HGMJJ9<=E=MJ=JHDMKA=MJK9FFW=K9N9FL<=<AKH9J9[LJ=TKGFLGMJ $DF=J=KL=J99DGJKIM= Do9FLA;GJHK9FLA #;LWEGAF<oMF=@WH9LAL=9F;A=FF= .ADo9FLA?XF=#=H=JKAKL=9M <=DT<= @MALT<APK=E9AF=K9HJXKDo9HH9JALAGF<=KKQEHL]E=K<=Do@WH9LAL=;o=KLIM=D9JWHDA;9LAGF NAJ9D=K=HGMJKMAL=LIMoMF=AF>=;LAGF;@JGFAIM=K=<WN=DGHH= 9FK;=;9KDo9FLA?XF=#K F=<AKH9J9[LJ9H9K=LDo9FLA;GJHK9FLA #KFo9HH9J9[LJ9H9K!A?MJ= '= H9KK9?= <= Do9FLA?XF= #K T Do9FLA #K =KL G:K=JNW H9J>GAK H=F<9FL D=K <=JFAXJ=K H@9K=K KHGFL9FWE=FL ;=LL= WNGDMLAGF K= HJG<MAL <9FK <=K ;9K H9J 9F '= HGJL=MJ AF9;LA>KGMN=FL9HH=DWhHGJL=MJK9AFi9<=KLJ9FK9EAF9K=KFGJE9D=KDo9FLA?XF=#K=KL HGKALA> Do9FLA?XF= #= =KL FW?9LA> =L Do) 1# =KL FW?9LA> $D =KL ;GFL9?A=MP =L Fo9 H9K LGMBGMJKMF>GA=FGJE9DTD9:AGHKA= NGDMLAGF<=KE9JIM=MJK/9:D=9M • 'o9FLA?XF= #K HJGMN= IM= D= NAJMK =KL HJWK=FL <9FK DoGJ?9FAKE= K9 H=JKAKL9F;= HDMK<=<=MPEGAK9HJXKDoAF>=;LAGF>9AL;J9AF<J=D=H9KK9?=TMF=>GJE=;@JGFAIM= • 'o9FLA;GJHK9FLA #K=KLMFAF<A;9L=MJ<oAEEMFAK9LAGF;GFLJ=D=1# • 'o9FLA?XF= #= LWEGA?F= <= D9 EMDLAHDA;9LAGF <M NAJMK =L <GF; <oMF JAKIM= <= ;GFL9?AGFAEHGJL9FL • 'o9FLA;GJHK9FLA #=KA?F9D=D9>AF<=D9HWJAG<=<=EMDLAHDA;9LAGFNAJ9D= • 'o9FLA;GJHK9FLA #;=KLMFKA?F=IM=DoGJ?9FAKE=9MFBGMJGMMF9MLJ=;JGAKWD= NAJMK<=Do@WH9LAL=E9AKADF=<ALH9KKAD9H=JKGFF==KLE9D9<=GM?MWJA= . . .

(93) 75B?37;JA7>B323:/?>B3B?@@J?7>B3@239J=/A7A3C7?/93/75B3@16J:/ 1<=7J23,

(94) -. 75B?37;JA7>B323@:/?>B3B?@@J?7>B3@/B1<B?@2B;36J=/A7A3C7?/93 16?<;7>B3@16J:/1<=7J23,

(95) - @=R D=K FGMJJAKKGFK AF>=;LWK DoWNGDMLAGF =KL @9:ALM=DD=E=FL LJXK <A>>WJ=FL= <= ;=DD= <=K 9<MDL=K JW;=EE=FL AF>=;LWK 'o9FLA?XF= #= H=JKAKL= '=K 9FLA;GJHK 9FLA #= . .

(96) Fo9HH9J9AKK=FL H9K KA?F9FL DoWNGDMLAGF ;@JGFAIM= DoU?= 9<MDL= =FKA= <M KM< =KL D9 KWJG;GFN=JKAGF <= Do9FLA?XF= #= =KL G:K=JNW= LQHAIM=E=FL =FLJ=

(97) =L

(98) 9FK E9AK Do9FLA?XF=#KH=JKAKL=D=HDMKKGMN=FL .

(99) "3@B?3239/16/?53C7?/93 '9IM9FLA>A;9LAGF<=D9;@9J?=NAJ9D=K=>9ALH9JD9E=KMJ=<=Do)<MNAJMK<9FKD=K9F? H9J Do9EHDA>A;9LAGF ?WFGEAIM= +- GM +GDQE=J9K= @9AF -=9;LAGF IMA D= L=KL D= HDMK K=FKA:D=KH=JE=LL=FL<=<WL=;L=J<=K;GF;=FLJ9LAGFKAF>WJA=MJ=KT

(100) ;GHA=K E' '=FGE:J=<=H9JLA;MD=KNAJ9D=K=KL=PHJAEW=FHMAKK9F;=<=

(101) GM=FW;@=DD=DG?9JAL@EAIM= 'GJKIM=D9;@9J?=NAJ9D=>DM;LM==FLJ=DoAF<WL=;L9:ADALW=L

(102)

(103)

(104)

(105) ;GHA=K EDKGAL

(106) GMDG? Do@WH9LAL==KL;GFKA<WJW=;GEE=AF9;LAN= M <=DT<=

(107)

(108)

(109)

(110)

(111) ;GHA=K EDKGAL

(112) GMDG? D9;@9J?=NAJ9D=H=ML9DD=J9M <=DT<=

(113) EADDA9J<K<=;GHA=K EDKGAL

(114)

(115) GM

(116) DG?=DD==KL ;GFKA<WJW=;GEE=9;LAN= FLJ=

(117)

(118)

(119)

(120) =L

(121)

(122)

(123)

(124)

(125) ;GHA=KKGAL=FLJ=

(126) =L

(127) GM=FLJ= =LDG?DoAFL=JHJWL9LAGF=KLHDMK<WDA;9L= 9FK;=JL9AFK;9K;=D9;GJJ=KHGF<TMF=@WH9LAL= AF9;LAN=<9FK<o9MLJ=KTMF=@WH9LAL=9;LAN=>9A:D=E=FLNAJWEAIM= .=MDMFKMANA<9FKD= L=EHK H=JE=L <= K= >9AJ= MF= A<W= 0F= ;@9J?= NAJ9D= IMA H9KK= <=

(128)

(129)

(130)

(131)

(132) T

(133)

(134)

(135)

(136)

(137) ;GHA=K;o=KLMF=;@9J?=NAJ9D=IMAF=:GM?=H9K +GMJIM=DoWNGDMLAGFKGALKA?FA>A;9LAN=AD >9MLIMo=DD=KGAL9MEGAFK<oMF>9;L=MJ

(138) M;GMJK<oMF=JW9;LAN9LAGFAD=PAKL=MF<W;9D9?= L=EHGJ=D 9N=; <o9:GJ< MF= 9M?E=FL9LAGF <= D9 ;@9J?= NAJ9D HMAK WN=FLM=DD=E=FL MF= 9M?E=FL9LAGF<=KLJ9FKEAF9K=K F;9K<o@WH9LAL=AF9;LAN=MF=9M?E=FL9LAGF<=D9;@9J?= NAJ9D= H=ML <GF; YLJ= 9FFGF;A9LJA;= <oMF= JW9;LAN9LAGF =L AEHGK= <= J9HHJG;@=J D9 KMJN=ADD9F;= )/093/B "/?>B3B?@@J?7>B3@7;A3?=?JA/A7<; "/?>B3B? @J?<9<57>B3. %J?7<23 2T7;1B0/A7<;. ;431A7<; /75BL. ;431A7<; ?J@<9B3. ;431A7<; 16?<;7>B3. +/117;/A7<;. #K? FLA #K FLA #;LGL9D FLA #; $?(. e . e . . e. . #=? FLA #:= #1 ). e e. . e e. e e . . . . .

(139) AA7AB23A6J?/=3BA7>B3 'G:B=;LA><MLJ9AL=E=FL<=DoAF>=;LAGF;@JGFAIM=H9JD=1#=KL<9EWDAGJ=JD9IM9DALW<=NA= =LD9KMJNA=<=D9H=JKGFF=AF>=;LW==FHJWN=F9FL=L=FDAEAL9FLD9HJG?J=KKAGF<=D9E9D9<A= N=JKD9;AJJ@GK=D9;AJJ@GK=<W;GEH=FKW=D=;9F;=J<M>GA=D=<W;XK=L9;;=KKGAJ=E=FL <=DAEAL=JD=JAKIM=<=LJ9FKEAKKAGF<M1#9MP9MLJ=KDo9HHJG;@=n/=KL9F</J=9LoFo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o@WH9LAL= 9A?MZ >MDEAF9FL=KHGMJ D=KIM=DD=KD9EAK==FJGML=<=LJ9AL=E=FL9FLANAJ9DHGMJJ9YLJ==FNAK9?W= 9FK;=KEYE=K >GJE=K9MHJGFGKLA;KHGFL9FWE=FLE9MN9AKD9LJ9FKHD9FL9LAGF@WH9LAIM=H=MLW?9D=E=FL YLJ=<AK;MLW=J '=LJ9AL=E=FL=KL?WFWJ9D=E=FLAF<AIMWHGMJD=KH=JKGFF=K;@JGFAIM=E=FLAF>=;LW=K9N=; H=JKAKL9F;=<oMFL9MPWD=NW<o'/=LMFFAN=9MWD=NW<)NAJ9D<M1#<9FKD=HD9KE9 A=FIM9M;MF<=KEW<A;9E=FLK<AKHGFA:D=KF=KGAL;9H9:D=<oWDAEAF=JDAF>=;LAGF;=JL9AFK EW<A;9E=FLKAF@A:=FLD9JWHDA;9LAGF<MNAJMK=LHJWNA=FF=FLD=K9LL=AFL=K<M>GA=;GEE=D9 ;AJJ@GK==LD=;9F;=J<M>GA= '=KLJ9AL=E=FLK9;LM=DD=E=FLMLADAKWKKGFL<=KEW<A;9E=FLK 9FLANAJ9MP L=DK IM= D= >ME9J9L= <= <AKGHJGPAD LWFG>GNAJ /! GM Do=FL=;9NAJ /1 =L D=K EG<MD9L=MJK <M KQKLXE= AEEMFAL9AJ= L=DK IM= DoAFL=J>WJGF 9DH@9 +=?AFL=J>WJGF 9D>9 9 /GML=>GAK;=JL9AF=KH=JKGFF=KKGFL:=9M;GMHHDMKKMK;=HLA:D=K<=JWHGF<J=IM=<9MLJ=K HGKKA:D=E=FL=FJ9HHGJL9N=;D=?WFGLQH=<MNAJMKGM<=D@WJW<ALW<MH9LA=FL '=LJ9AL=E=FL 9?AL=FJW<MAK9FLD9JWHDA;9LAGFNAJ9D= '9LJ9FKHD9FL9LAGF@WH9LAIM==KLAF<AIMW==F;9K<= ;AJJ@GK=KWNXJ=<o@WEGJJ9?A=<A?=KLAN=GM<o=F;WH@9DGH9L@A=;GEHDAIM9FLD9;AJJ@GK= DD= HGK==KK=FLA=DD=E=FLD=HJG:DXE=<=D9JW;A<AN=<=DoAF>=;LAGFH9JD=1#KMJD=?J=>>GF . .

(140).

(141) '=KAF<A;9LAGFK<MLJ9AL=E=FLJ=HGK=FL?WFWJ9D=E=FLKMJD9;GE:AF9AKGF<=LJGAK;JALXJ=K D=KL9MPKWJAIM=K<)<M1#D=KL9MPKWJAIM=K<'/D9KWNWJALW<=D9E9D9<A=@WH9LAIM= WN9DMW= ;DAFAIM=E=FL H9J :AGHKA= @WH9LAIM= GM H9J <=K EWL@G<=K FGF AFN9KAN=K '=K AF<A;9LAGFK <M LJ9AL=E=FL <GAN=FL W?9D=E=FL HJ=F<J= =F ;GEHL= DU?= DWL9L <= K9FLW D=K 9FLW;W<=FLK >9EADA9MP <= # GM <= ;AJJ@GK= =L D=K E9FA>=KL9LAGFK =PLJ9 @WH9LAIM=K /9:D=9M67 /9:D=9M$F<A;9LAGFK<=LJ9AL=E=FLHGMJD=KH9LA=FLK;@JGFAIM=E=FLAF>=;LWKH9JD=1# (A/23@23 9T6J=/A7A3 16?<;7>B3. +# * :9. !). AJJ@GK= <W;GEH=FKW=. WL=;L9:D=. ,M=D;GFIM=. /J9AL=J. AJJ@GK= ;GEH=FKW=. WL=;L9:D=. ,M=D;GFIM=. /J9AL=J. -W9;LAN9LAGF KWNXJ=<= Do@WH9LAL= ;@JGFAIM=. WL=;L9:D=. #WH9LAL=FGF ;AJJ@GLAIM= ;@JGFAIM==L? #=HGKALA>. . . . . . .

(142)

(143)

(144)

(145) .

(146)

(147)

(148) l

(149)

(150)

(151)

(152) . D=NW. )?/7A3:3;A. /J9AL=J. PN9D=MJ KMHWJA=MJ= <=D9DAEAL= <=D9FGJE9D=. *:K=JN9LAGFH=F<9FLEGAKKA9M;MFHJG:DXE=<= <W;GEH=FK9LAGF@WH9LAIM= /J9AL=JKAD=K'/ J=KL=FLWD=NW=K *:L=FAJDo@AKLGDG?A=GMWN9DM=JD9 >A:JGK=<=E9FAXJ=FGFAFN9KAN=9 SN9DM=JD9>A:JGK=<=E9FAXJ=FGFAFN9KAN= lPN9D=MJ .MJN=ADD=JLGMKD=KEGAK AGHKA=KAD=KL=KLKFGF KMHWJA=MJ= AFN9KA>KKM??XJ=FLMF=>A:JGK=KA?FA>A;9LAN='/ <=D9DAEAL= WD=NW=KU?=9FKGM9FLW;W<=FL>9EADA9D<= <=D9FGJE9D= #GM<=;AJJ@GK=<M>GA= /J9AL=J=F;9K<AF>D9EE9LAGFEG<WJW=TKWNXJ=GM <=>A:JGK=KA?FA>A;9LAN=9 SN9DM=JD9>A:JGK=<=E9FAXJ=FGFAFN9KAN= )GJE9D9?= .MJN=ADD=JLGMKD=KEGAK AGHKA=KAD=KL=KLKFGF

(153) H@9K= AFN9KA>KKM??XJ=FLMF=>A:JGK=KA?FA>A;9LAN=GMKADQ <oAEEMFG 9MF9FLW;W<=FL>9EADA9D<=#GM;AJJ@GK= LGDWJ9F;= /J9AL=J=F;9K<AF>D9EE9LAGFEG<WJW=TKWNXJ=GM <=>A:JGK=KA?FA>A;9LAN=9. ,M=D;GFIM=. P;DMJ=<9MLJ=K;9MK=K<'/WD=NW=K SN9DM=JD9 >A:JGK=<=E9FAXJ=FGFAFN9KAN= .MJN=ADD=JLGMKD=K EGAK AGHKA=KAD=KL=KLKFGFAFN9KA>KKM??XJ=FL MF=>A:JGK=KA?FA>A;9LAN=U?=9FK'/WD=NW=K <=>9VGFH=JKAKL9FL=GM9FLW;W<=FL>9EADA9D<= #GM<=;AJJ@GK= /J9AL=J=F;9K<AF>D9EE9LAGF EG<WJW=TKWNXJ=GM<=>A:JGK=KA?FA>A;9LAN=9. .

(154) .

(155)

(156)

(157) . )GJE9D. . . )GJE9D.

(158)

(159)

(160) . . #WH9LAL= ;@JGFAIM=FGF ;AJJ@GLAIM==L ?#=FW?9LA>. .

(161)

(162)

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