• No results found

Prediction of outcome in genetic cardiac diseases

N/A
N/A
Protected

Academic year: 2022

Share "Prediction of outcome in genetic cardiac diseases"

Copied!
157
0
0

Laster.... (Se fulltekst nå)

Fulltekst

(1)

#

!#"#

!#

(2)

© Ana Monica Chivulescu, 2021

Series of dissertations submitted to the

Faculty of Mathematics and Natural Sciences, University of Oslo No. 896-0

ISSN 1501-7710

All rights reserved. No part of this publication may be

reproduced or transmitted, in any form or by any means, without permission.

Cover: Hanne Baadsgaard Utigard.

Print production: Reprosentralen, University of Oslo.

(3)

!

# # #

!#

" ! "" !!!

$%

$%

$%

"

$%

$%

$%

!#!

$%

$%

$%

!#%$'

"''&'"

+%&'

* ) %&'

# '%!#"'#%"

"'%( %%%,'!&

%"&'#%#%#%$,

%!"'%&#""

! "

#

$%

$%

$%

(4)

$%

$%

$%

"

&&$"'%""! ,!!%&

! %&&$%#%&&#""$%#"&"! ,!!%&

%%,'!%&"$'"'&*'&&$%#%&&#"

'% '(%&"$'"'&*'%(&,"%#!

'%('(% "("'#" "#%! '&"$'"'&*'%(&,"%#!

%'#"#)"'%( %%%,'!&"%(&,"%#!

$%) "#!'% ""( (&&("'#"

% %#%')"'&"$'"'&*'!'% ""( (&&("'#"

"#%!'% ) )&(%%,"$'"'&*'!'% ""( (&&("'#"

(%%"#)"'%( %%%,'!&

''%"&#&&$"'%"

)"#&&$%#%&&#"

%#"&&''(&"%&#%&)%%%,'!&

%%,'!#"%#!,#$',%(&,"%#!#)% $

'%"''%%,'!#"%#!,#$',"%(&,"%#!

"!"'#$'"'&*'%(&,"%#!

)%&&(% #('#!

)%&&$"#',$

)%&%%,'!#('#!

!

!#

$%

$%

$%

(5)

!

!#!

$%

$%

$%

(6)
(7)

!

0ABLPHKDP:LI>K?HKF>=:MMA>>GMK>?HK:K=BHEH@B<:E%GGHO:MBHGPAB<AE:M>K

;><:F>,KH<:K=BH>GMK>?HK%GGHO:MBHG >I:KMF>GMH?:K=BHEH@R:M+LEH1GBO>KLBMR

$HLIBM:E 1GBO>KLBMRH?+LEHPBMAMA>LNIIHKMH?/HNMA!:LM>KG*HKP:R.>@BHG:E$>:EMA NMAHKBMR

%MA:L;>>G:GAHGHNK?HKF>MH;>@NB=>=;RMPH;KBEEB:GMLNI>KOBLHKL0A>BKLNIIHKM

=B=GHMHGER:EEHPF>MH:<<HFIEBLAMABLPHKD;NMFHLMBFIHKM:GMERBMLAB?M>=FRP:RH?

MABGDBG@?KHF:LMKB<MERF>=B<:EK>:LHGBG@MH:L<B>GMB?B<:G=<K>:MBO>I>KLI><MBO>

LLH<B:M>,KH?>LLHK'KBLMBG:$:N@::A:L;>>GFRF:BGLNI>KOBLHK KHE>FH=>E:G=

FRF:LM>K=NKBG@MABLMBF>/A>BL$>:=H?MA>K>L>:K<A@KHNI?HK<:K=BH@>G>MB<L:G=LN==>G

<:K=B:<=>:MA:G= BK><MHKH?,KH:K=BH>GMK>?HK%GGHO:MBHG/A>BL:LDBE?NEK>L>:K<A>K L<B>GMB?B<PKBM>K:G=:LN<<>LL?NEBGM>KG:MBHG:EHIBGBHGF:D>KBGMA>?B>E=H?@>G>MB<<:K=B:<

=BL>:L>L:G=<:K=B:<:KKARMAFB:L3HK=L<:GGHM>QIK>LLFR@K:MBMN=>:G=:IIK><B:MBHGMH RHN0A:GDRHN?HKRHNKMBF> ?HK:EEMA>DGHPE>=@>RHNLA:K>=PBMAF>:G=:EEMA>

BGO>LMF>GMLRHNF:=>BGF>

,KH?>LLHK0AHK!=O:K=L>GA:L;>>GFR<HLNI>KOBLHK <HF>GMHK:G=?:<BEBM:MHK$>BL MA>$>:=H?MA>:K=BHEH@R >I:KMF>GM:M+LEH1GBO>KLBMR$HLIBM:E:G=A:L<HG=N<M>=

>GMK>?HK:K=BHEH@B<:E%GGHO:MBHG NKBG@FR,A A>:ELHA:L;>>GMA>,K>LB=>GMH?MA>

!NKHI>:GLLH<B:MBHGH?:K=BHO:L<NE:K%F:@BG@$>BL:PHKE=PB=>K><H@GBS>=>QI>KMBGMA>

?B>E=H?<:K=BHEH@R:G=<:K=B:<BF:@BG@%:FAHGHNK>=:G=MA:GD?NEMA:MRHN<AHHL>F>MH

;>RHNK,A LMN=>GM:G=?HNG=MA>MBF>MHLNI>KOBL>F>:EHG@MA>P:R

%:FMA:GD?NEMH'BKLM>G'KHA@/dK>GL>G:G=$>E@>/DNELM:=?HKMA>BK<HGMKB;NMBHGMH MABLMA>LBL%P:GMMHMA:GDMH_ROBG=(B>?HKI:MB>GMERLNIIHKMBG@F>BGMA>E>:KGBG@IKH<>LL BGMA>>:KER=:RLH?FRK>L>:K<ACHNKG>R:G=?HKABL<HGMKB;NMBHGMH:EEFRI:I>KLPBMA K>F:KD:;E>BGLB@AML%A:O>MH@BO>O>KRLI><B:EMA:GDLMH!LMA>K/<A>BKERG<DPBMAPAHF%

(8)

<HEE:;HK:M>=MB@AMER:G=PAH>G<HNK:@>=F>MH;><HF>MA>K>L>:K<A>K%:FMH=:R%A:=:

@K>:M<HEE:;HK:MBHGPBMAAKBLMBG>.HHMP>EM*HK;>K@:G=">==H'BKD>ELPAHPHKD>=PBMAF>

HGMA>L:F>IKHC><M:G=<HGMKB;NM>=PBMAMA>BKDGHPE>=@>:G=:F:SBG@IHLBMBOBMRMHHNK K>LNEML!RLM>BG/DCdELOBD:G=(:KL#NGG:K'Ec;H>:K>MA>>QI>KB>G<>=<HEE>:@N>L%<HNE=

:EP:RL:LD?HK:=OB<>%MP:L:IE>:LNK>MH;>I:KM(:KL >C@::K=]LIKHC><MPAHINMLHFN<A

>??HKM:G=I:LLBHGBGABLPHKD0HO>!EBL:;>MA$NGM:G=!BOBG=:;>E:K>FRH??B<>

<HEE>:@N>L:G=FR<EHL>?>EEHPL0A:GDLMHMA>F%A:O>:EP:RLEHHD>=?HKP:K=MH<HFBG@MH PHKDLI><B:EMA:GDLMH):K@:K>MA.B;> HNKK>L>:K<AGNKL> ):KB:.NN= <HHK=BG:MHKH?

,KH:K=BH>GM>K?HK%GGHO:MBHG:G=,BKBMM:*R;>K@ :=FBGBLMK:MHKH?>GMK>?HK

:K=BHEH@B<:E%GGHO:MBHG ?HKMA>BKDBG=LNIIHKM:G=@K>:M:=OB<> >:KG=>KLC>KKBG@

):KB:GG>"HKLU /MB:G.HLL ,UEK>DD> E>LLB:-N:MMKHG> %LHMM::LMKBGB 'KBLMH??>K G=K>L>G &HKNG0:G@>G:G=)B*@NR>G PBMAHNMRHNMA>K>L>:K<A>GOBKHGF>GMPHNE=GHM A:O>;>>G<HFIE>M>

%:F@K:M>?NEMH.NQ:G=K:&NK<NM:G=H@=:G,HI>L<N?KHFMA>%GLMBMNM>?HK

:K=BHO:L<NE:K BL>:L>L N<A:K>LM .HF:GB:PAHLNIIHKM>=F>BG;><HFBG@:<:K=BHEH@BLM :G=I:O>=FRP:RMHP:K=L:AB@AJN:EBMRF>=B<:EK>L>:K<A:G=<EBGB<:EIK:<MB<>

%:F@K:M>?NEMHFRI:K>GML NFBMK::G=KBLMB:G PAH:EP:RLLNIIHKM>=F>BG

>O>KRMABG@%BGM>G=>=:G=F:=>LNK>%PHNE=:EP:RL@>MMA>;>LMBGEB?>0HFR=>:K;KHMA>K

>S:K PAHBLMA>FHLMBGM>EEB@>GM:G=BGLB@AM?NEI>KLHG%DGHP0A:GDRHN?HKBGLIBKBG@F>

0HMA>I:MB>GMLPAHMKNLM>=HNKPHKD:G=<HGL>GM>=MH;>I:KMH?MA>L>IKHC><ML

(9)

$B@AI>G>MK:G<>:G=LBFBE:K=BL>:L>IKH@K>LLBHGBGIKH;:G=L:G=?:FBERF>F;>KL PBMA:KKARMAFH@>GB<<:K=BHFRHI:MARABONE>L<N) (B>_$ ,HI>L<N /DNELM:=

$ !=O:K=L>G0 &NK<NM.+ $:N@::'$!NK$>:KM&IK

=HB>NKA>:KMC>AS=HB>NKA>:KMC>AS

3HKL>,KH@GHLBLBGKN@:=:LRG=KHF>I:MB>GMLPBMA:KKARMAFH@>GB<<:K=BHFRHI:MAR

?>:MNK>L/<A>BKERG<D! ABONE>L<N) (B>_ )HMH< 'HNE:EBL& =>LFNG=BL /B>BK:& AB>K<AB:& KN@:=:, HLRGL !=O:K=L>G0 KHH@F:GL/ $:N@::

'$&EBG!E><MKHIARLBHE+<M=HB CC:<>I

)BMK:E:GGNENL=BLCNG<MBHGBL:LLH<B:M>=PBMA:=O>KL>HNM<HF>BG):K?:G:G=(H>RLf B>MSLRG=KHF>LABONE>L<N) 'KHA@/dK>GL>G' /<A>BKERG<D! (BG=;>K@.

>C@::K=( (B>_$ $>EE>2:EE>0 /DCdELOBD!0 !LM>GL>G)! !=O:K=L>G0 (BG@::L,/ $:N@::'$!NK$>:KM&:K=BHO:L<%F:@BG@ ><C>::=HB

>AC<BC>::

(10)

:KKARMAFH@>GB<<:K=BHFRHI:MAR K/KN@:=:LRG=KHF>

!#>E><MKH<:K=BH@K:F

"*?B;KBEEBG

( /(H>RL B>MSLRG=KHF>

) FBMK:E:GGNENL=BLCNG<MBHG )"/):K?:GLRG=KHF>

0#"\MK:GL?HKFBG@@KHPMA?:<MHK\>M:

(11)

0ABLMA>LBL?H<NL>LHGMA>IKH@GHLBLH?I:MB>GMLPBMA@>G>MB<=BL>:L>LH?MA>A>:KM :KKARMAFH@>GB<<:K=BHFRHI:MAR,:I>K KN@:=:LRG=KHF>K/I:I>K:G=MA>

FHLMIK>O:E>GMBGA>KBM>=<HGG><MBO>MBLLN>=BLHK=>KL ):K?:GLRG=KHF>)"/:G=(H>RL B>MSLRG=KHF>( /%GI:I>K =BL>:L>IKH@K>LLBHG:G=:KKARMAFB<HNM<HF>H??:FBER F>F;>KLH?I:MB>GMLPBMA:K><HFI:K>=PBMAMAHL>H?IKH;:G=LPAH:K>DGHPGMHA:O>

FHK>L>O>K>=BL>:L>IA>GHMRI>L,:I>KBGO>LMB@:M>LMA>IKH@GHLMB<O:EN>H??>:MNK>LBG I:MB>GMLPBMAK/,:I>K>QIEHK>LMA>BFI:<MH?FBMK:E:GGNENL=BLCNG<MBHG) :

<HG=BMBHGH?M>G:LLH<B:M>=PBMAFBMK:EO:EO>IKHE:IL> HGMA>HNM<HF>H?I:MB>GMLPBMA)"/

:G=( /":M:E:KKARMAFB:L:MRHNG@:@>:K>:K><H@GBS>=<:NL>H?=>:MABGI:MB>GMLPBMA :G=K/:K=B:<BGOHEO>F>GMBLMA>F:BG<:NL>H?=><K>:L>=LNKOBO:EBGI:MB>GMLPBMA)"/

:G=( />MM>K<A:K:<M>KBL:MBHGH?MA>HNM<HF>:G=B=>GMB?B<:MBHGH?IKH@GHLMB<F:KD>KL:K>

G><>LL:KR?HK>:KERBGM>KO>GMBHG:G=IK>O>GMBHGH??:M:E>O>GMLBGMA>L>I:MB>GML

# # #

BL:IKH@K>LLBO>BGA>KBM>==BL>:L>H?MA>A>:KMFNL<E>0A>BG=BOB=N:E:??><M>=;R BL;HKGPBMA:@>G>MB<IK>=BLIHLBMBHG H?M>G:@>G>MB<FNM:MBHGBGHG>H?MA>@>G>L

>G<H=BG@MA><:K=B:<=>LFHLHF>L >LFHLHF>L:K>IKHM>BGLK>LIHGLB;E>?HKBGM>K<>EENE:K :=A>LBHG:G=<HFFNGB<:MBHGBGMA>A>:KM0A>ONEG>K:;E>=>LFHLHF>L=BLKNIMNG=>K

BG<K>:L>=P:EELMK>LLE>:=BG@MH<:K=BHFRH<RM>L=>M:<AF>GM:G=LN;L>JN>GM:IHIMHLBL 0A>E:<DH?<>EENE:K<HGM:<MMKB@@>KL:=BIH@>G>LBL:G=MA>GHKF:E<:K=B:<MBLLN>BL

IKH@K>LLBO>ERK>IE:<>=;R?B;KH?:MMRMBLLN>

0A>=B:@GHLBLH??H<NL>LHGKB@AMO>GMKB<E>BFI:BKF>GM:G=BL>LM:;EBLA>=;RNLBG@

:L>KB>LH?>E><MKB<:E :KKARMAFB< FHKIAHEH@B<:E ABLMHEH@B<:E:G=?:FBERABLMHKR<KBM>KB:

>LM:;EBLA>=;RMA>0:LD"HK<>HGL>GLNLBG0:;E>%GBML<E:LLB<:EIA>GHMRI>

(12)

:??><MLIK>=HFBG:GMERMA>KB@AMO>GMKB<E>:G=F:GB?>LMLPBMAKB@AMO>GMKB<E>=BE:M:MBHG:G=

BFI:BK>=<HGMK:<MBEBMR$HP>O>K BMBLGHPK><H@GBS>=MA:ME>?MO>GMKB<E>BL:??><M>=BG FHK>MA:GH?<:L>L >O>G?KHF>:KER=BL>:L>IA:L>L

0A>HGL>MH?=BL>:L>BLGHM;>?HK>:=HE>L<>G<>(B?>MAK>:M>GBG@O>GMKB<NE:K :KKARMAFB:L<:G;>MA>?BKLMF:GB?>LM:MBHGH?=BL>:L>BGIK>OBHNLER:II:K>GMERA>:EMAR BG=BOB=N:EL)HKIAHEH@B<:E:G=LMKN<MNK:E:;GHKF:EBMB>LH?MA>A>:KMFB@AM;>:;L>GMBGMABL

>:KER=BL>:L>IA:L>$HP>O>K BGMABL>E><MKB<:ELM:@> LN;ME>LMKN<MNK:E:;GHKF:EBMB>L<:G;>

IK>L>GM+NKK>L>:K<A@KHNIA:O>LAHPGMA:MLN;ME>:;GHKF:EBMB>LEBD>

A>M>KH@>G>BMRBGFRH<:K=B:E<HGMK:<MBHGDGHPG:LF><A:GB<:E=BLI>KLBHG:K>IK>L>GM?KHF

>:KER:G=BG=B<:M>:AB@A:KKARMAFB<KBLD%GMA>G:MNK:E<HNKL>H?MA>=BL>:L> >E><MKB<:E

<A:G@>LIK><>=>=>O>EHIF>GMH?LMKN<MNK:E:;GHKF:EBMB>L%GMA>LMKN<MNK:ELM:@> KB@AM O>GMKB<NE:K=BE:M:MBHG:G==RL?NG<MBHG;><HF>:II:K>GM%GMABLLM:@> MA>?B;KH?:MMRL<:KBG@BL

<HGLB=>K>=MA>F:BGLN;LMK:M>?HKO>GMKB<NE:K:KKARMAFB:L0A>=BL>:L><:G?NKMA>KIKH@K>LLMH :G>G=LM:@>PBMA?:BEBG@A>:KM

>?HK>MA>NL>H?@>G>MB<M>LMBG@HG:E:K@>L<:E> I:MB>GMLPBMAP>K>FHLMER IK>L>GMBG@BG:=O:G<>==BL>:L>LM:@>LPBMA:L>O>K>ER=BE:M>=:G==RL?NG<MBHG:EKB@AM O>GMKB<E>:L<:=>@>G>MB<L<K>>GBG@BG?:FBERF>F;>KLH?FNM:MBHGIHLBMBO>I:MB>GML LAB?M>=MA>IHINE:MBHG?KHFI:MB>GMLPBMA?NEER>QIK>LL>=IA>GHMRI>MH@>G>MB<:EER IK>=BLIHL>=BG=BOB=N:EL:G=I:MB>GMLPBMA=B:@GHL>=BG>:KER=BL>:L>IA:L>L0ABL H;L>KO:MBHGE>=MHMA><HG<ENLBHGMA:MIKH;:G=L:K>FHK>L>O>K>ER:??><M>=MA:G?:FBER

F>F;>KL$HP>O>K MA>G:MNK:EABLMHKRH?MA>=BL>:L>BG?:FBERF>F;>KLBLIHHKER=>L<KB;>=

BL>:L>I>G>MK:G<>O:KB>L;>MP>>GBG=BOB=N:EL:G=BL:@>=>I>G=>GM 0A>KBLD H?=BL>:L>I>G>MK:G<>BG:GBG=BOB=N:EPAHBGA>KBM>=:=>LFHLHF:EFNM:MBHGBLLMBEENGDGHPG 0A>IA>GHMRIB<:EL>O>KBMRO:KB>L;>MP>>GBG=BOB=N:ELPBMA=B??>K>GM@>G>MB<FNM:MBHGL:G=

>O>G;>MP>>G<:KKB>KLH?MA>L:F>@>G>MB<FNM:MBHG?KHFMA>L:F>?:FBERLN@@>LMBG@HMA>K

(13)

?:<MHKLMHIE:R:KHE>BG=BL>:L>F:GB?>LM:MBHG0A>K>:K><NKK>GMERGH>LM:;EBLA>=IK>=B<MHKLH?

L>O>K>=BL>:L>IKH@K>LLBHG

.>@NE:K?HEEHPNIOBLBMLBGBG=BOB=N:EL:MKBLDH?=>O>EHIBG@MA>=BL>:L>:G=BG I:MB>GMLPBMAHNMABLMHKRH?L>O>K>O>GMKB<NE:K:KKARMAFB:LA:O>MA>:BFMHB=>GMB?RBG=BOB=N:EL :MAB@A:KKARMAFB<KBLD;>?HK>MA>H<<NKK>G<>H??BKLML>O>K>:KKARMAFB<>O>GMBGHK=>KMH IK>O>GMLN==>G<:K=B:<=>:MA):G:@>F>GMFNLM;>BG=BOB=N:EBL>=PBMAK>@:K=MHMA>

KBLDH?=BL>:L>I>G>MK:G<>:G=MHMA>L>O>KBMRH?=BL>:L>IKH@K>LLBHG.>I>:M>=?HEEHPNIL FB@AM;>:;NK=>GBGBG=BOB=N:EL:MEHPKBLDH?=>O>EHIBG@MA>=BL>:L>$HP>O>K K>@NE:K F>=B<:EOBLBML:K>G>>=>=BGI:MB>GMLPBMAAB@AKBLDH?=>O>EHIBG@:G:KKARMAFB<IA>GHMRI>

%=>GMB?B<:MBHGH?IK>=B<MHKLH?=BL>:L>IKH@K>LLBHGBLG>>=>=BGHK=>KMHBG=BOB=N:EBS>?HEEHP NI

.><>GMER :G:KKARMAFB<KBLD<:E<NE:MHK?HKKBLD:LL>LLF>GMH?BG<B=>GM:KKARMAFB<

>O>GMLA:L;>>G=>O>EHI>= KKARMAFB<KBLDBL:LL>LL>=MAHN@ABGM>@K:MBHGH?<EBGB<:E I:K:F>M>KLL>Q K><>GM<:K=B:<LRG<HI> >E><MKB<:EI:K:F>M>KL>QM>G=>=0P:O>BGO>KLBHGBG KB@AMIK><HK=B:EE>:=L AB@A;NK=>GH?IK>F:MNK>O>GMKB<NE:K<HGMK:<MBHGL:M$HEM>KFHGBMHKBG@

:G=GHGLNLM:BG>=O>GMKB<NE:KM:<AR<:K=B::G=BF:@BG@I:K:F>M>KL=><K>:L>=KB@AMO>GMKB<E>

>C><MBHG?K:<MBHG;R<:K=B:<F:@G>MB<K>LHG:G<><:K=B:<F:@G>MB<K>LHG:G<>>O:EN:MBHGBL G><>LL:KR?HKMA><:E<NE:MBHGH?:KKARMAFB<KBLDL<HK>EM>KG:MBO>ER :KKARMAFB<KBLD

:LL>LLF>GM;RMHHEL>:LBER:O:BE:;E>BG<EBGB<:EIK:<MB<>BLG>>=>=

!#

K/BLF:BGER:G>E><MKB<:E=BL>:L>:LLH<B:M>=PBMAMRIB<:E>E><MKH<:K=BH@K:F!#

I:MM>KGH?<HO>=/0L>@F>GM>E>O:MBHGBGKB@AMIK><HK=B:EE>:=LIHLBMBHG>=BGL><HG= MABK=HK

?HNKMABGM>K<HLM:ELI:<> 0A>MRIB<:E!#I:MM>KGBL<:NL>=;R:A>M>KH@>GHNL

K>IHE:KBL:MBHG:G=:=>E:R>=<HG=N<MBHGBGMA>KB@AMO>GMKB<NE:KHNM?EHPMK:<M>IB<:K=BNF

(14)

K/BL:LLH<B:M>=PBMAKBLDH?EB?>MAK>:M>GBG@O>GMKB<NE:K:KKARMAFB:LBGRHNG@BG=BOB=N:EL 0ABLIA>GHMRI>BL:MMKB;NM>=MH:EHLLH??NG<MBHGH?LH=BNF*:<A:GG>E:G=MH:

K>=N<MBHGH?MA>*:<NKK>GMK/BL<:NL>=BGH?<:L>L;R:FNM:MBHGBGMA>

LH=BNFOHEM:@>@:M>=<A:GG>E:EIA:LN;NGBM/*@>G><H=BG@?HKMA>kLN;NGBMH?MA>

*:<A:GG>E

0A><:K=B:<=>LFHLHF>L:G=MA>*:<A:GG>E<HFIE>Q:K>I:KMH?MA>BGM>K<:E:M>=

=BL<L :LMKN<MNK>LBMN:M>=:MMA>BGM>K<>EENE:KCNG<MBHG PAB<A:LLNK>L<>EEMH<>EE:=A>LBHG:G=

IKHI:@:MBHGH?MA>>E><MKB<:EBFINEL>BGMA>A>:KM"B@NK>0A><:K=B:<=>LFHLHF>L :G=MA>*:<A:GG>E<HFIE>Q:K><EHL>ERBGM>K<HGG><M>=:G=HI>K:M>:L:LBG@E>NGBMR <:EE>=

MA><HGG>QHF>MB@AMBGM>K:<MBHG;>MP>>GMA><HGG>QHF>]L>E>F>GML>QIE:BGLMA>

K>=N<MBHGBG*:<NKK>GMBGMA>IK>L>G<>H?=>?><M>==>LFHLHF>L0ABLBLIHLLB;ER K>LIHGLB;E>?HKMA>>E><MKB<:EBGLM:;BEBMRBGMA>:;L>G<>H?FHKIAHEH@B<:E<A:G@>LBG>:KER HKK>LIHG=BG@ER :=BL>:L>=*:<A:GG>EFB@AM:EM>KBGM>K<>EENE:K:=A>LBHG?NG<MBHGH?

=>LFHLHF>LE>:=BG@MHLMKN<MNK:E:;GHKF:EBMB>LBGI:MB>GMLPBMAK/:G=K/:K>

MAHN@AMMH;>=BLMBG<MF:GB?>LM:MBHGLH?:=BL>:L>LI><MKNF<:NL>=;RFHE><NE:K:EM>K:MBHGLH?

MA><HGG>QHF>

%MA:L;>>GARIHMA>LBS>=MA:MMA><HFFHGI:MAHIARLBHEH@B<:EI:MAP:RBGK/:G=

>QIE:BGLKB@AMO>GMKB<NE:KLMKN<MNK:E:;GHKF:EBMB>LBGI:MB>GMLPBMAK/0ABLK:BL>LMA>

JN>LMBHGH?PA>MA>KK/<:GIKH@K>LL?KHF:INK>ER>E><MKB<:E<HG=BMBHGMH:GEBD>

IA>GHMRI>=BK><M<HFI:KBLHG;>MP>>GK/:G=PHNE=>EN<B=:M>AHPF:GRH?MA>

I:MB>GMLPBMAK/A:O>=>O>EHI>=?>:MNK>LBGMA><HNKL>H?MA>=BL>:L>

Gap junction Desmosome

53A>1&/419-@5/05-3>-9?4;C5:3@41@45345:@1>/;::1/@5;:

;2@4101?9;?;91?;>-:31-??A>5:3-041?5;:;2-06-/1:@

/->05;9E;/E@1?-:0!-/4-::18.8A1-:03-<6A:/@5;:3>1E

>1?<;:?5.812;>@41<>;<-3-@5;:;2@41-/@5;:<;@1:@5-8

(15)

'-.815-3:;?@5/-83;>5@495:->>4E@49;31:5//->05;9E;<-@4E-:0>A3-0-?E:0>;91

==4D?49;31:5//-=05;9D;<-?4D =@3-0->D:0=;91

5-3:;>?5//=5?1=5-

'1A5>10)->7;=/1=5?1=5- (4-:34-5(/;=1>D>?19

85:5/-845>?;=D

-=05-/-==1>?<;8D9;=<45/*) *<?>

==4D?495/<?> @:/81-=91/4-:5>9<?>>D:/;<1 #;/?@=:-8-3;:-8=1><5=-?5;:><?>

?=5-825.=588-?5;: 28@??1=D<?>

%=1/;=05-8)+ H*9-6;= (<;:?-:1;@>?D<1<-??1=:<?>

%=1/;=05-8)+ H*;=H*B5?4';=)+ **95:;= 1A1=5:0@/10?D<1<-??1=:<?>

<>58;:B-A1**9-6;= =@35:0@/10?D<1<-??1=:<?>

)H9>1/ !-?1<;?1:?5-8>95:;=

==4D?495->

*) #(*)!<-??1=:>@<1=5;=-C5>9-6;=

*) #(*)!<-??1=:5:21=5;= @:7:;B:-C5>95:;=

%*> 4-?;8?1=9;:5?;=5:395:;=

(?=@/?@=-8-.:;=9-85?51>

75:1>5-0D>75:1>5-;=-:1@=D>9-:0(1A1=18D058-?10'*;=(1A1=18D 59<-5=10'*2@:/?5;:9-6;=

75:1>5-0D>75:1>5-;=-:1@=D>9-:0"5808D058-?10'*A;8@91;=

"5808D59<-5=10'*2@:/?5;:95:;=

-958D45>?;=D

%-?4;31:5/9@?-?5;:9-6;= %-?4;31:5/9@?-?5;:<?>

;:25=9105:-013=11=18-?5A1/85:5/-88D-?

-@?;<>D >@=31=D9-6;=

;:25=910=(5:- 013=11=18-?5A1<?>

(@><1/?105:-013=11=18-?5A1/85:5/-88D;=0@1?;(D95:;=

;:25=9105:-013=11=18-?5A195:;=

(@><5/5;@><?> @:1C<8-5:10<?>(5:- 013=11=18-?5A1

5-3:;>5>

125:5?19-6;=9-6;=-:095:;=;=95:;= 125:5?1H<?>

;=01=85:19-6;=-:095:;=;=95:;= %=;.-.81H<?>

%;>>5.819-6;=;=95:;= %;>>5.81<?>

..>1B5-@5;:?->>4E@49;31:5//->05;9E;<-@4E>&>A3-0-?E:0>;91181/@>;/->05;3>-9)B1:@>5/A8->

25.>588-@5;:)'B1:@>5/A8->@-/4E/->[email protected]:081.>-:/4.8;/7!&)':;:?A?@-5:10)'<@?<;5:@?#)?

<>19-@A>1B1:@>5/A8->/;:@>-/@5;:?%>[email protected]:081.>-:/4.8;/7%)>534@B1:@>5/81&?A001:/->05-/01-@4'

@1>95:-8-/@5B-@5;:0A>-@5;:'*'C-B15:B1>?5;:

(16)

LBG MA>F:CHKBMRH?K/I:MB>GML:K>GHP:=:RL?:FBERF>F;>KLB=>GMB?B>=

MAKHN@A<:L<:=>@>G>MB<L<K>>GBG@):GRH?MA>F:K>EHPKBLDBG=BOB=N:ELPBMAHNM:

LIHGM:G>HNLMRIB<:E!#I:MM>KG$BLMHKRH?EB?>MAK>:M>GBG@:KKARMAFB:L:G=>OB=>G<>H?:

LIHGM:G>HNLMRIB<:E!#BG:LRFIMHF:MB<K/I:MB>GM:K><E>:KER:LLH<B:M>=PBMAAB@A :KKARMAFB<KBLD=KN@BG=N<>=!#I:MM>KGBL:LLH<B:M>=PBMAEHP>K:KKARMAFB<KBLD :EMAHN@A:<>KM:BGKBLDLMBEE>QBLML !#FB@AMA:O>:EHPL>GLBMBOBMR?HK=>M><MBG@

:KKARMAFB<LN;LMK:M>LBGK/>MM>KLMK:MB?B<:MBHGMHHEL:K>MA>K>?HK>G>>=>=/N;ME>LMKN<MNK:E

<A:G@>LFB@AM;>MA>LN;LMK:M>?HKMA>>E><MKB<:E:;GHKF:EBMB>L:G=:ELHH?L>O>K>:KKARMAFB:L BGK/=O:G<>=BF:@BG@M><AGBJN>LFB@AM;>FHK>L>GLBMBO>MA:GMA>!#BG=>M><MBG@MA>

=BL>:L>LN;LMK:M>IK>=BLIHLBG@MH:KKARMAFB:LBGK/3>ARIHMA>LBS>MA:MLMKN<MNK:E

:;GHKF:EBMB>LFB@AM;>:F:KD>KH?AB@A:KKARMAFB<KBLD>O>GBGMA>:;L>G<>H?:MRIB<:E!#

I:MM>KGBGI:MB>GMLPBMAK/

" !

)"/:G=( /:K>MA>FHLM<HFFHGBGA>KBM>=<HGG><MBO>MBLLN>=BLHK=>KL)"/BL

<:NL>=;RFNM:MBHGLBGMA>@>G><H=BG@?HK?B;KBEEBG"* :@ER<HIKHM>BG:MM:<ABG@

LFHHMAFNL<E>L<>EELMH>E:LMBG:G=<HEE:@>GBGMA>>QMK:<>EENE:KF:MKBQ0A><HGG><MBHG

;>MP>>G:=>?><MBO>"*:G=HMA>K>QMK:<>EENE:KF:MKBQ<HFIHG>GMLBLIKHG>MHKNIMNK>

E>:=BG@MH=>@>G>K:MBHGH?MA>>QMK:<>EENE:KF:MKBQ"*IKHM>BG:ELH:LLNK>LMA>

BGM>@KBMRH?<HGG><MBO>MBLLN>LMAKHN@AK>@NE:MBHGH?MK:GL?HKFBG@@KHPMA?:<MHK\>M:0#"\

I:MAP:RLB@G:EEBG@=>?><MBO>"*IKHM>BG?:BELMHL>JN>LM>K0#"\BGMA>>QMK:<>EENE:K F:MKBQBG<K>:LBG@0#"\;BH=BLIHGB;BEBMR:G=>GA:G<BG@0#"\LB@G:EEBG@E>:=BG@MH:;GHKF:E

=>@K:=:MBHGH?MA>>QMK:<>EENE:KF:MKBQ

(17)

0A>=B:@GHLBLH?)"/BLF:=>NLBG@MA>.>OBL>=#A>GMKBM>KB:B?>BMA>K:

?:FBERABLMHKRHK:=BE:M>=:HKM:MH@>MA>KPBMA:"*@>G>FNM:MBHG ><MHIB:E>GLBLHK LRLM>FB<?>:MNK>L:K>IK>L>GM

( /P:L?BKLM=>L<KB;>=:L:GHO>KE:IIBG@LRG=KHF>PBMA)"/;>BG@<:NL>=;R:

I>KMNK;:MBHGBGMA>LB@G:EEBG@H?0#"\I:MAP:R( /P:L<E:LLB?B>=BGMRI>L:<<HK=BG@

MHMA>@>G>MB<=>?><MBGOHEO>=FNM:MBHGLBGMA>@>G>L<H=BG@?HK0#"\K><>IMHKL:G=

:G=:K>K>LIHGLB;E>?HK( /MRI>:G=K>LI><MBO>ER FNM:MBHGLBGMA>

#%)'( $()&$)&" %#%"%@>G><H=BG@?HKMA>L><HG=:KR F>LL>G@>KH?MA>0#"\I:MAP:R:K>:LLH<B:M>=PBMA( /MRI>:G==>?><MLBG0#"\@>G>

>G<H=BG@MA>0#"\I:MAP:REB@:G=:K>:LLH<B:M>=PBMA( /MRI>G BG<K>:L>=0#"\LB@G:EEBG@BL:<HFFHGI:MAHIARLBHEH@B<:EI:MAP:RBG)"/:G=( /

I:MAH@>GB<FNM:MBHGBG<HF;BG:MBHGPBMA>BMA>K:G:HKMB<I:MAHEH@RHKMRIB<:E LRLM>FB<<A:K:<M>KBLMB<L:K>G><>LL:KR?HKMA>=B:@GHLBLH?( /BG:IKH;:G=( /<:G

;>:ELH=B:@GHL>=BG:FNM:MBHGIHLBMBO>?:FBERF>F;>KPBMA:?:FBERABLMHKRH?( / :<<HK=BG@MH(H>RL B>MS.>OBL>=*HLHEH@R

,KH@K>LLBO>=>@K:=:MBHGH?MA>>QMK:<>EENE:KF:MKBQBLK>LIHGLB;E>?HK:HKMB<=BE:M:MBHG :G=FRQHF:MHNL=>@>G>K:MBHGH?MA>FBMK:EO:EONE:KMBLLN>PBMAE>:?E>MMAB<D>GBG@:G=

>EHG@:MBHGH?<AHK=:>M>G=BG>:>E>:=BG@MHFBMK:EO:EO>IKHE:IL>BG;HMA)"/:G=( /

"B@NK>%GM>K>LMBG@ER :G>Q<>LLBO>0#"\LB@G:EEBG@A:L;>>GLN@@>LM>=MH;>:IHLLB;E>

NG=>KERBG@I:MAHIARLBHEH@B<:EF><A:GBLFH?FRQHF:MHNL=>@>G>K:MBHG:ELHBGGHG LRG=KHFB<FBMK:EO:EO>IKHE:IL>

"" !!!

)BMK:EO:EO>IKHE:IL> =>?BG>=:LMA>:MKB:E=BLIE:<>F>GM≥FFH?:GRI:KMH?MA>

E>:?E>M;>RHG=FBMK:E:GGNENLBGLRLMHE> A:L:IK>O:E>G<>H?BGMA>@>G>K:E

(18)

IHINE:MBHG:G=:FN<AAB@A>KIK>O:E>G<>BGBGA>KBM>=<HGG><MBO>MBLLN>=BLHK=>KL;>BG@

FHLMIK>O:E>GMBG)"/;NM:ELH?K>JN>GMER?HNG=BG( /0A>@>G>MB<

IK>=BLIHLBMBHGMH=>@>G>K:MBHGH?MA>>QMK:<>EENE:KF:MKBQ>QIE:BGLMA>AB@AIK>O:E>G<>H?

FRQHF:MHNL=>@>G>K:MBHGH?MA>FBMK:EO:EO>BGMA>L>MMBG@H?BGA>KBM>=<HGG><MBO>MBLLN>

=BLHK=>KL

) :G:GHF:ERH?MA>:MKBHO>GMKB<NE:KCNG<MBHG P:L?BKLM=>L<KB;>=BG:NMHILB>=

A>:KMLI><BF>GL:L:L>I:K:MBHGH?MA>:MKBNFFBMK:ECNG<MBHG?KHFMA>O>GMKB<NE:K

FRH<:K=BNF) P:L?K>JN>GMER?HNG=BG:LLH<B:MBHGPBMAFRQHF:MHNL:G=IKHE:IL>=

FBMK:EO:EO>L%MA:L;>>GARIHMA>LBS>=MA:M:=><HNIE>=FBMK:E:GGNENL?KHFMA>

O>GMKB<NE:KFRH<:K=BNFBGLRLMHE>IK>=BLIHL>LMHBG<K>:L>=ARI>KFH;BEBMRH?MA>FBMK:E :II:K:MNL:G=<HGMBGNHNLE>:?E>M:G=M>GLBHGH?<AHK=:>M>G=BG>:>E>:=BG@MHO:EONE:K

=>@>G>K:MBHG

3>ARIHMA>LBS>MA:M BGMA>

IK>L>G<>H?:=>?><MBO><HGG><MBO>

MBLLN> MA>:MKBHO>GMKB<NE:KO:EO>LE:<D MA>LNIIHKMIKHOB=>=;RMA>?B;KHNL LD>E>MHGH?MA>A>:KME>:=BG@MH:

=><HNIE>=FBMK:E:GGNENL?KHFMA>

O>GMKB<NE:KFRH<:K=BNF0ANL MA>

AB@AIK>O:E>G<>H?FBMK:EO:EO>

BGOHEO>F>GM<HNE=:ELH;>?:OHNK>=

;R:AB@AIK>O:E>G<>H?)

,K>O:E>G<>H?) BG)"/:G=( / BLNGDGHPG

53A>1&/419-@5/<5/@A>1588A?@>-@5:3@E<5/-8/->05;B-?/A8->

-.:;>9-85@51?5: ->2-:?E:0>;913)!03$&$0!0#(.4!1"3+!0 1612$,-$22$01++3120!2$#3,!-!2'.+.&6/#!2$##(2(.-12

(19)

) P:L?HNG=MH;>IK>L>GMBG:EFHLM:EEI:MB>GMLPBMAL>O>K>FBMK:EO:EO>=BL>:L>

=N>MHGHGLRG=KHFB<IKHE:IL>0A>F:@GBMN=>H?MA>=BLCNG<MBHGHK) =BLM:G<>

F>:LNK>=?KHFMA>:MKBNFFBMK:ECNG<MBHGMHMA>O>GMKB<NE:KFRH<:K=BNF:M>G=LRLMHE>

<HKK>E:M>=PBMAMA>L>O>KBMR:G=>QM>G=H?MA>O:EONE:K=>@>G>K:MBHG0A>L>?BG=BG@L LN@@>LML>O>K>=>@>G>K:MBO>FBMK:EO:EO>=BL>:L>G>>=BG@FBMK:EO:EO>LNK@>KRMH;>:

<HFIEB<:MBHGH?FBMK:EO:EO>IKHE:IL>:G=) .><>GMLMN=B>LA:O>K>O>:E>=L>O>K>

O>GMKB<NE:K:KKARMAFB:L:G=LN==>G<:K=B:<=>:MAMH;>:GHMA>K<HFIEB<:MBHGH?GHG

LRG=KHFB<FBMK:EO:EO>IKHE:IL>%MA:L;>>GLN@@>LM>=MA:MLMK>M<ABG@H?MA>O>GMKB<NE:K FRH<:K=BNF:G=I:IBEE:KRFNL<E>L;R:=>M:<A>=FBMK:E:GGNENLBG=N<>LO>GMKB<NE:K><MHIR

;RMKB@@>K>=:<MBOBMR:G=<HGMKB;NM>LMHIKH@K>LLBO>FRH<:K=B:E?B;KHLBL :IHLLB;E>LN;LMK:M>

H?:KKARMAFB:L;RF:<KHK>>GMKR"NKMA>KFHK> K>FH=>EEBG@H?MA>E>?MO>GMKB<E>BGHK=>K MH:<<HFFH=:M>E:K@>FBMK:EK>@NK@BM:GMOHENF>L<:GE>:=MHBGM>KLMBMB:E?B;KHLBL :GHMA>K IHLLB;E>LN;LMK:M>?HK:KKARMAFB:L;RMKB@@>K>=:<MBOBMR:G=>GA:G<>=:NMHF:MB<BMR

%G)"/:G=( / G:MNK:EABLMHKRH?MA>=BL>:L>BL=HFBG:M>=;R:HKMB<=BL>:L>

$HP>O>K FBMK:EO:EO>=BL>:L>BL:GHMA>KBFIHKM:GM<HFHK;B=BMRPBMA?K>JN>GMG>>=?HK

<:K=B:<LNK@>KR%G:==BMBHG LN==>G<:K=B:<=>:MA:G=L>O>K>:KKARMAFB:L:K>HMA>K

<:NL>LH?=>:MABG)"/,A>GHMRIB<:E<A:K:<M>KBL:MBHGH?)"/:G=( /BGK>E:MBHGPBMA ) <HNE=;>H?<EBGB<:EK>E>O:G<>

(20)

0A>@EH;:E:BFH?MABLMA>LBLP:LMH=>L<KB;>=BL>:L>HNM<HF>BGI:MB>GMLPBMA@>G>MB<

<:K=B:<=BL>:L>L:LLH<B:M>=PBMAKBLDH?LN==>G<:K=B:<=>:MA:MRHNG@:@>3>:ELH:BF>=MH

?BG=IK>=B<MHKLH?AB@AKBLD?HKLN==>G=>:MA:G=:=O>KL>>O>GMLBGMABLIHINE:MBHG3>

BGM>G=>=MHIKHIHL>>:KERBGM>KO>GMBHGBGAB@AKBLDI:MB>GMLBGHK=>KMHIK>O>GMLN==>G=>:MA :G=MHBFIKHO>LNKOBO:E

,:I>K

3>:BF>=MH=>L<KB;>=BL>:L>I>G>MK:G<>BGFNM:MBHGIHLBMBO>?:FBERF>F;>KLPBMA :G=<HFI:K>=BL>:L>IKH@K>LLBHG;>MP>>GIKH;:G=LPBMA:G=MA>BKFNM:MBHGIHLBMBO>

?:FBERF>F;>KL3>ARIHMA>LBS>=MA:M=BL>:L>I>G>MK:G<>BLAB@ABG?:FBERF>F;>KL:G=

IKH;:G=L:G=?:FBERF>F;>KLA:O>LBFBE:K=BL>:L>IKH@K>LLBHG3>:ELH:BF>=MHK>E:M>

:KKARMAFB<KBLD:G=LMKN<MNK:E=BL>:L>IKH@K>LLBHGARIHMA>LBSBG@MA:MLMKN<MNK:EIKH@K>LLBHGBL :LLH<B:M>=PBMAAB@A:KKARMAFB<KBLD

,:I>K

3>BGM>G=>=MH>QIEHK>MA>IK>L>G<>H?>E><MKB<:E:G=LMKN<MNK:E<KBM>KB:BGI:MB>GML PBMAK/=>M>KFBGBG@MA>HO>KE:I;>MP>>G:G=K/3>ARIHMA>LBS>=MA:MI:MB>GMLPBMA K/IK>L>GMBG@>E><MKB<:E:G=LMKN<MNK:E<A:K:<M>KBLMB<LBG<EN=>=BG0:LD"HK<>

KBM>KB:A:O>PHKL>IKH@GHLBLMA:GK/I:MB>GMLPBMAHNM?>:MNK>L

(21)

,:I>K

3>:BF>=MH=>L<KB;>IK>O:E>G<>H?) BGI:MB>GMLPBMA)"/:G=( /:G=:ELHMH BGO>LMB@:M>MA>HNM<HF>H?I:MB>GMLPBMAK>@:K=MHMA>IK>L>G<>H?) 3>ARIHMA>LBS>=

MA:MIK>O:E>G<>H?) BLAB@ABGI:MB>GMLPBMA)"/:G=( /:G=MA:MIK>L>G<>:G=

F:@GBMN=>H?) :K>:LLH<B:M>=PBMAPHKL>IKH@GHLBL

(22)

"

,:I>K

0H>O:EN:M>=BL>:L>I>G>MK:G<>BG?:FBERF>F;>KL:MBG<ENLBHG:G=:ME:LM?HEEHPNI 0H=>L<KB;>MA>IK>L>G<>H?>E><MKB<:E:;GHKF:EBMB>L:G=H?LMKN<MNK:E:G=?NG<MBHG:E

:;GHKF:EBMB>LBG<EN=>=BG0:LD"HK<>KBM>KB::M?BKLM:G=E:LM>Q:FBG:MBHG:G=MH K>I>:M>=ERF>:LNK>D>R><AH<:K=BH@K:IAB<I:K:F>M>KL=NKBG@?HEEHPNI

0H:LL>LL:KKARMAFB<KBLDBGI:MB>GMLPBMAGHHKFBE=LMKN<MNK:E:;GHKF:EBMB>L:M BG<ENLBHGPAH=>O>EHI>=:==BMBHG:ELMKN<MNK:E<KBM>KB:O>KLNLMAHL>PAH=B=GHM

=>O>EHIG>PLMKN<MNK:E:;GHKF:EBMB>L=NKBG@?HEEHPNI

,:I>K

0HK>IHKMMA>IK>O:E>G<>H?K>IHE:KBL:MBHG:G==>IHE:KBL:MBHG<KBM>KB: H?L>O>K>ER :G=FH=>K:M>ER=BE:M>=KB@AMO>GMKB<NE:KHNM?EHPMK:<M:G=H?L>O>K>ER:G=FH=>K:M>ER K>=N<>=?K:<MBHG:E:K>:<A:G@>BGK/I:MB>GMLPBMA:G=PBMAHNMO>GMKB<NE:K

:KKARMAFB:L

!LMBF:M>LNKOBO:E?K>>H?L>O>K>O>GMKB<NE:K:KKARMAFB:LBGK/I:MB>GMLPBMA:G=

PBMAHNM>E><MKB<:E<KBM>KB: PBMA:G=PBMAHNM=BE:M>=KB@AMO>GMKB<NE:KHNM?EHPMK:<M :G=PBMA:G=PBMAHNMK>=N<>=?K:<MBHG:E:K>:<A:G@>

0H<HFI:K>MA>IK>=B<MBHGKBLD?HKO>GMKB<NE:K:KKARMAFB:H?:FH=>EBG<EN=BG@

LRG<HI>:G=MRI>!#I:MM>KGPBMAMA>IK>=B<MBHGKBLD?HK:KKARMAFB:LH?:FH=>E BG<EN=BG@LRG<HI> MRI>!#I:MM>KG:G=LMKN<MNK:E:;GHKF:EBMB>LBGI:MB>GMLPBMA K/

(23)

,:I>K

0HK>E:M>MA>IK>L>G<>H?) PBMA:HKMB<=BL>:L>:HKMB<=BLL><MBHG:G=IKHIARE:<MB<

:HKMB<LNK@>KR:G=FBMK:EO:EO>LNK@>KRBGI:MB>GMLPBMA)"/:G=( /

(24)

!#!

/MN=RI:KMB<BI:GMLPBMABG<EN=>=BGMA>,:I>K:G=P>K>K><KNBM>=:MMA>

>I:KMF>GMH?:K=BHEH@R +LEH1GBO>KLBMR$HLIBM:E .BDLAHLIBM:E>M *HKP:R,:MB>GMLPBMA K/?KHF,:I>KP>K>BG<EN=>=:M1GBO>KLBMR$HLIBM:EKNLL>EL 1GBO>KLBM:BK6B>D>GANBL KNLL>E >E@BNF,:MB>GML)"/:G=( /BG<EN=>=BG,:I>KP>K>K><KNBM>=:MMA>

>I:KMF>GMH?:K=BHMAHK:<B<LNK@>KR +LEH1GBO>KLBMR$HLIBM:E .BDLAHLIBM:E>M *HKP:R ):G:@>F>GM:G=<EBGB<:E<:K>P>K>=><B=>=;RMA>MK>:MBG@IARLB<B:GHG<EBGB<:EBG=B<:MBHG

,:I>K

%G=BOB=N:ELLNLI><M>=PBMAP>K>K>?>KK>=MHHNK<>GMK>?HK=B:@GHLBL:G=?NKMA>K MA>K:I>NMB<F:G:@>F>GM,:MB>GML=B:@GHL>=PBMA:?M>K:G=MA>BKFNM:MBHGIHLBMBO>

?:FBERF>F;>KLP>K>BG<EN=>=BGHNK=:M:;:L>LM:KMBG@?KHF"HKMABLLMN=R I:MB>GMLP>K>K>MKB>O>=?KHFMA>=:M:;:L>BG ><>F;>KRMA>MBF>PA>GMABLLMN=R P:LLM:KM>=MA>=:M:;:L>BG<EN=>=I:MB>GML0A>LMN=RBL;:L>=HGMA><HAHKMH?

I:MB>GMLL>E><M>=?HKMA>LMN=RH?(B>>M:E/>O>GI:MB>GMLP>K>>Q<EN=>==N>MH

<:K=BHINEFHG:KR<HFHK;B=BMB>L:G=I:MB>GMLP>K>EHLMMH?HEEHPNI:G=MA>K>?HK>>Q<EN=>=

?KHFMA>BGBMB:E<HAHKM0A>I:MB>GMLPBMAHNM:<HFIE>M>?HEEHPNI>O:EN:MBHGBG<EN=BG@

><AH<:K=BH@K:IARP>K>>Q<EN=>=+?MA>FI:MB>GMLA:=;:L>EBG>O>GMKB<NE:K:KKARMAFB:L :G=P>K>MA>K>?HK>>Q<EN=>=:ELH?KHFMA>LMN=RH?(B>>M:EPABE>I:MB>GMLPBMAHNM O>GMKB<NE:K:KKARMAFB:L:M;:L>EBG>BG<EN=>=BGMA>LMN=RH?(B>>M:EP>K>>Q<EN=>=?KHF MABLLMN=R=N>MHFBLLBG@?HEEHPNI><AH<:K=BH@K:IARMMA>MBF>H?MABLLMN=R G>P I:MB>GMLA:=;>>GBG<EN=>=BGMA>=:M:;:L>H?PAB<AHGERI:MB>GMLA:=:ME>:LMHG>?HEEHPNI

><AH<:K=BH@K:IAR:G=JN:EB?B>=?HKBG<ENLBHGBGMABLLMN=R0ANL MA>?BG:E<HAHKMBG<EN=>=

(25)

I:MB>GMLEE>EB@B;E>I:KMB<BI:GMLA:=>BMA>K=>?BGBM>=B:@GHLBLH?HK:I:MAH@>GB<

FNM:MBHG:LLH<B:M>=PBMA"B@NK>

53A>1:/8A?5;:-83;>5@495:#-<1>..>1B5-@5;:->>4E@49;31:5//->05;9E;<-@4E

,:I>K

"HKMABLLMN=RP><HGLB=>K>=MA>BG<ENLBHGH?I:MB>GML?KHF,:I>K+?MA>

I:MB>GML P>K>>Q<EN=>==N>MHFBLLBG@!#=:M:E>:=BG@MHMA>BG<ENLBHGH?

I:MB>GMLBGMA>?BG:E:G:ERLBL

K/I:MB>GML?KHFMA>IK>OBHNLLMN=RH?/<A>BKERG<A>M:EP>K><HGLB=>K>=?HK BG<ENLBHGBGMABLLMN=R+?MA>I:MB>GMLPBMAK/ I:MB>GMLP>K>H??>K>=:<HFIE>M>

K>O:EN:MBHGBG<EN=BG@:<:K>?NE:LL>LLF>GMH?>E><MKB<:E:G=LMKN<MNK:E<KBM>KB:+?MA>L>

K/I:MB>GMLP>K>>Q<EN=>==N>MH<HG<HFBM:GM<HKHG:KR:KM>KR=BL>:L>@BOBG@:MHM:EH?

K/I:MB>GML>EB@B;E>?HKBG<ENLBHGBGMA>?BG:E:G:ERLBL"B@NK>

(26)

53A>18;C/4->@;25:/8A?5;:;2>A3-0-?E:0>;91<-@51:@?-:0->>4E@49;31:5//->05;9E;<-@4E<-@51:@?-:0;B1>8-<

C5@4<>1B5;A?<A.85/-@5;:?"'$(0+6-"*$2!++(-+$"20./'61(.+#.())!"$/ (2'/$0,(11(.-

,:I>K

,:MB>GMLK>?>KK>=MHMA> >I:KMF>GMH?:K=BHMAHK:<B</NK@>KR +LEH1GBO>KLBMR

$HLIBM:E .BDLAHLIBM:E>M:LA:OBG@)"/:G=K>E:M>=<HG=BMBHGL:G=I:MB>GMLLNLI><M>=PBMA ):K?:GEBD>:HKMHI:MARP>K>IKHLI><MBO>ERK><KNBM>=LBG<>RMA>=:M>PA>GMABLLMN=R LM:KM>=MA>=:M:;:L>H?MA> >I:KMF>GMH?:K=BHMAHK:<B</NK@>KRBG<EN=>=I:MB>GMLH?:EE :@>L%GHK=>KMH;>>EB@B;E>?HKMABLLMN=R I:MB>GMLA:=MH?NE?BE.>OBL>=#A>GMKBM>KB:?HK )"/:G=(H>RL B>MS.>OBL>=*HLHEH@R?HK( /0H:LLNK>AHFH@>G>BMRH?MA>

LMN=RIHINE:MBHGP>>Q<EN=>=I:MB>GMLPBMAG>HG:M:E)"/:G=I:MB>GMLPBMA:LLH<B:M>=

<HFHK;B=BMB>L<HKHG:KR:KM>KR=BL>:L>:G=M:<AR<:K=B:BG=N<>=<:K=BHFRHI:MARG

><AH<:K=BH@K:IAB<>Q:FBG:MBHGP:L:O:BE:;E>BG:EE;NMI:MB>GML0ANL P>P>K>?BG:EER :;E>MHBG<EN=>I:MB>GMLPBMA)"/:G=PBMA( /?HKMABLLMN=R"B@NK>

(27)

53A>18;C/4->@;2?@A0E91@4;0;8;3E-:005?@>5.A@5;:;295@>-8-::A8A?05?6A:/@5;:5:<-@51:@?C5@4 ->2-:?E:0>;91-:0

;1E?51@F?E:0>;91'(43+$1"3$2!+30$!02!0#(.4!1",!&(-&#.( $')"()$!! (2'/$0,(11(.-

(28)

>FH@K:IAB<=:M:

EEI:MB>GMLI:KMB<BI:M>=BGF>=B<:EBGM>KOB>PLPAB<A:EEHP>=NLMHH;M:BG<EBGB<:E

<A:K:<M>KBLMB<L:@> L>Q IKH;:G=LM:MNL:EHG@PBMAI:MB>GM:G=?:FBERABLMHKR,:MB>GMLPBMA )"/:G=( /NG=>KP>GMIARLB<:E>Q:FBG:MBHG:BFBG@MHK>O>:EL>E><MBO>LRLM>FB<?>:MNK>L BG<EN=>=BG=BL>:L><KBM>KB:,:I>K >FH@K:IAB<:G=<EBGB<:E=:M:P>K>>QMK:<M>=?KHF

>E><MKHGB<F>=B<:E?BE>L

#>G>MB<M>LMBG@

#>G>MB<M>LMBG@P:LI>K?HKF>=BGI:MB>GML,:I>K:G= I:MB>GMLPBMAK/

,:I>K:G=BGI:MB>GMLPBMA)"/:G=( /,:I>K

#>G>MB<M>LMBG@P:LI>K?HKF>=BGIKH;:G=LIK>L>GMBG@PBMA<:K=B:<IA>GHMRI>

<HGLBLM>GMPBMA,:I>K:G=0A>@>G>I:G>E<HO>K>=&"!%& " $@>G>

(#%" $@>G> (#%&"! $@>G>:G=(#%%"" $@>G>":FBER F>F;>KLH?FNM:MBHGIHLBMBO>I:MB>GMLP>K>B=>GMB?B>=MAKHN@A<:L<:=>@>G>MB<L<K>>GBG@:G=

BG<EN=>=B?FNM:MBHGIHLBMBO>

EEI:MB>GML=B:@GHL>=PBMAK/;:L>=HG:LIHGM:G>HNLHK=KN@BG=N<>=MRI>!#

I:MM>KGP>K>@>G>MB<:EERM>LM>=?HKHG>H?MA>FNM:MBHGL:LLH<B:M>=PBMAK/0A>@>G>I:G>E BG<EN=>=@>G> ! $($%'&'%) $ @>G><H=BG@?HK:IKHM>BG

BGOHEO>=BGMA>K>@NE:MBHGH?MA>=>E:R>=K><MB?B>KIHM:LLBNF<A:GG>E "+'%"&%(&) +'%$(" !@>G><H=BG@?HK:IKHM>BGK>@NE:MBG@<:K=B:<*:<NKK>GM:G=

$!+' $@>G>>G<H=BG@:IKHM>BGBGOHEO>=BGMA>*:<A:GG>EMK:??B<DBG@

,:MB>GML=B:@GHL>=HKLNLI><M>=PBMA)"/NG=>KP>GM@>G>MB<M>LMBG@?HK@>G>

(29)

HO>KE:IIBG@PBMA)"/:G=I:MB>GMLPBMA?>:MNK>LLN@@>LMBO>?HK( /P>K>M>LM>=?HK

FNM:MBHGLBG:G=@>G>L#>G>MB<M>LMBG@;RAB@AfMAKHN@AINML>JN>G<BG@

P:LBGMKH=N<>=BG:G=MA>@>G>I:G>EP:L>QM>G=>=MHBG<EN=>@>G>:G=

@>G>:LLH<B:M>=PBMA( /IA>GHMRI>

+GERI:MB>GMLPBMA<E:LLI:MAH@>GB<:G=<E:LLEBD>ERI:MAH@>GB<@>G>MB<

FNM:MBHGLP>K>=>?BG>=:LFNM:MBHGIHLBMBO>

!Q>K<BL>=:M:

%G,:I>K>Q>K<BL>=:M:<HEE><MBHGP:LI>K?HKF>=:L=>L<KB;>=BGIK>OBHNL

IN;EB<:MBHGL +NK@KHNIA:LIK>OBHNLERLAHP>=MA:MAB@ABGM>GLBMR>Q>K<BL>BGM>GLBMR A:LMA>FHLMA:KF?NE>??><MHGIA>GHMRI> 0A>K>?HK> ABLMHKRH?AB@ABGM>GLBMR

>Q>K<BL>>QIHLNK>F>M:;HEB<>JNBO:E>GML)!0LBGMA>R>:KLIKBHKBG<ENLBHG IK>OBHNLER K><HK=>=?KHFF>=B<:EBGM>KOB>PL P:LNL>=BGMABLLMN=R

0P>EO>E>:=K>LM!#

%G:EE:G=K/I:MB>GMLBG<EN=>=BG,:I>K:G=P>K><HK=>=MA>IK>L>G<>H?

F:CHKK>IHE:KBS:MBHG:;GHKF:EBMB>L0P:O>BGO>KLBHGBGKB@AMIK><HK=B:EE>:=L22BGMA>

:;L>G<>H?KB@AM;NG=E>;KNG<A;EH<D:G=FBGHKK>IHE:KBL:MBHG<A:G@>L0P:O>BGO>KLBHGBG 2:G=2 0P:O>BGO>KLBHGBG22HK0P:O>BGO>KLBHGBG22BGMA>IK>L>G<>H?

KB@AM;NG=E>;KNG<A;EH<DBG<EN=>=BGMA>0:LD"HK<>KBM>KB:0A>L:F>E>:=

!#L>KO>=?HKB=>GMB?B<:MBHGH?>ILBEHGP:O>=>?BG>=:L:EHP:FIEBMN=>LB@G:E;>MP>>GMA>

>G=H?MA>-./:G=MA>;>@BGGBG@H?MA>0P:O>BGKB@AMIK><HK=B:EE>:=L:G=?HK

B=>GMB?B<:MBHGH?M>KFBG:E:<MBO:MBHG=NK:MBHG≥FL><F>:LNK>=?KHFMA>G:=BKH?MA>/P:O>

MHMA>>G=H?MA>-./BGKB@AMIK><HK=B:EE>:=LBGMA>:;L>G<>H?KB@AM;NG=E>;KNG<A;EH<D

(30)

:<<HK=BG@MHMA>0:LD"HK<>KBM>KB:"B@NK>%G/MN=R !#P:LI>K?HKF>=:M BG<ENLBHG:G=:ME:LM?HEEHPNI0A>@:BGH?G>PFBGHKHKF:CHK>E><MKB<:E<KBM>KB:=NKBG@

?HEEHPNIP:L=>?BG>=:L>E><MKB<:EIKH@K>LLBHG

%G:EE:G=K/BG,:I>K MA>!#K><HK=BG@L?KHFBG<ENLBHGP>K>NL>=?HKMA>

B=>GMB?B<:MBHGH?<HO>=/0L>@F>GM>E>O:MBHGBGKB@AMIK><HK=B:EE>:=LIE:<>=BGMA>L><HG=

MABK=HK?HNKMABGM>K<HLM:ELI:<>

%G:==BMBHG P>F>:LNK>=,.BGM>KO:E -./<HFIE>Q:G=-0<BGM>KO:E=NK:MBHG:G=

A>:KMK:M>BG:EEI:MB>GMLBG,:I>K

53A>188A?@>-@5;:;2@41-??1??10181/@>;/->05;3>-9-:01/4;/->05;3>-<4E<->-91@1>?C45/4->1@E<5/-88E-??;/5-@10C5@4

>A3-0-?E:0>;91812@->>4E@49;31:5//->05;9E;<-@4E/1:@1>;>->1:;:?<1/525/>534@"'$(0+6-"*$2!++(- +$"20./'61(.+#.())!"$/ (2'/$0,(11(.-

$HEM>KFHGBMHKBG@

%G,:I>K $HEM>KFHGBMHKBG@P:L:O:BE:;E>BG:LN;L>MH?I:MB>GML:MBG<ENLBHG :G=:ME:LM?HEEHPNI0A>IK>L>G<>H?O>GMKB<NE:KIK>F:MNK><HGMK:<MBHGLBGAP:L

(31)

=>?BG>=:L:FBGHK:KKARMAFB:<KBM>KBNF >O>EHIF>GMH?:FBGHK:KKARMAFB:<KBM>KBNFH?

IK>F:MNK>O>GMKB<NE:K<HGMK:<MBHGLBGA:M$HEM>KFHGBMHKBG@=NKBG@?HEEHPNIGHM IK>L>GM:MBG<ENLBHGP:L<HGLB=>K>=:LB@GH?>E><MKB<:EIKH@K>LLBHG

%G,:I>K $HEM>KFHGBMHKBG@P:LI>K?HKF>=HG<EBGB<:EBG=B<:MBHGLBG:LF:EELN;L>M H?I:MB>GMLPBMALRFIMHFLLN@@>LMBO>?HK:KKARMAFB:L

2>GMKB<NE:K:KKARMAFB:L

%G,:I>K:G= L>O>K>O>GMKB<NE:K:KKARMAFB:LP>K>=>?BG>=:L:;HKM>=<:K=B:<

:KK>LM O>GMKB<NE:K?B;KBEE:MBHG LNLM:BG>=O>GMKB<NE:KM:<AR<:K=B:KNGLH?O>GMKB<NE:K;>:ML

;IF?HKL><HG=L<:IMNK>=HG!# $HEM>KFHGBMHKBG@HKBFIE:GM:;E><:K=B:<

=>?B;KBEE:MHKFHGBMHKBG@HK:IIKHIKB:M>% MA>K:IR:GMBM:<AR<:K=B:I:<BG@HK>E><MKB<:E LAH<DHMAL>O>K>O>GMKB<NE:K:KKARMAFB:L:MBG<ENLBHG:G==NKBG@?HEEHPNIP>K>K><HK=>=

BGMA>?BKLM,:I>KL"B@NK>%G,:I>K P>K><HK=>=BG<B=>GML>O>K>O>GMKB<NE:K

:KKARMAFB:L=NKBG@?HEEHPNI:KKARMAFB<HNM<HF>:G=MA>MBF>MH?BKLM:KKARMAFB<>O>GMBG IK>OBHNLER:KKARMAFB:?K>>I:MB>GML@>:M:KKARMAFB<>O>GMP:LK><HK=>=BGK/

I:MB>GML,:I>K%G,:I>K O>GMKB<NE:K:KKARMAFB:LP>K>=>?BG>=:LGHGLNLM:BG>=

O>GMKB<NE:KM:<AR<:K=B: <HFIE>QO>GMKB<NE:K><MHIB<;>:MLB>;B@>FBGR MKB@>FBGR:G=

<HNIE>MLHKIK>F:MNK>O>GMKB<NE:K<HGMK:<MBHGLI>KAHNK

(32)

53A>181/@>;/->05;3>-9-@99?-:0B1:@>5/A8->@-/4E/->05-;2>A3-0-?E:0>;91<-@51:@?C5@4<;??5.81@;-:0

>A3-0-?E:0>;91<-@51:@C5@4.;>01>85:1-:005-3:;?5?;2->>4E@49;31:5//->05;9E;<-@4E"'$(0+6-"*$2!++(- +$"20./'61(.+#.())!"$/ (2'/$0,(11(.-

0K:GLMAHK:<B<><AH<:K=BH@K:IAR

EELMN=RI:KMB<BI:M>=NG=>KP>GMMK:GLMAHK:<B<><AH<:K=BH@K:IARHG<EBGB<:E

BG=B<:MBHG0A>><AH<:K=BH@K:IAB<>Q:FBG:MBHGLP>K>I>K?HKF>=HG2BOB=!!L<:GG>KL :G=:G:ERL>=H??EBG>NLBG@#!$>:EMA<:K>!<AH,:<O>KLBHGHK;EBG=>=MHHNM<HF>L G:ERLBLH?BG<ENLBHG><AH<:K=BH@K:IAB>LBGI:MB>GML,:I>K:G=LM:KM>=PBMA MA>PHKDH?/:;>KGB:D>M:E P:L<HGMBGN>=;R(B>>M:E:G=P:L<HFIE>M>==NKBG@=:M:

:G:ERLBL?HK,:I>KEE:O:BE:;E>?HEEHPNI><AH<:K=BH@K:IAB<>Q:FBG:MBHGLBGI:MB>GML ,:I>KP>K>LN;L>JN>GMER:G:ERL>=;RMA>L:F>HI>K:MHK!<AH<:K=BH@K:IAB>LBGK/

I:MB>GML,:I>KP>K>:G:ERL>=;R:LBG@E>HI>K:MHK:M1GBO>KLBMR$HLIBM:EKNLL>EL

(33)

KARMAFP>K>BG<EN=>=BGMA>:G:ERLBL,:I>K:G="HK,:I>K :G:ERLBLH??BKLM

><AH<:K=BH@K:IAR:O:BE:;E>:MHNK<>GMK>BGI:MB>GMLPBMA)"/:G=( /P:L<HFIE>M>=;R HG>HI>K:MHK:M+LEH1GBO>KLBMR$HLIBM:E .BDLAHLIBM:E>M *HKP:R

%G,:I>K:G= P>:LL>LL>=KB@AMO>GMKB<E>LBS>;RKB@AMO>GMKB<E>HNM?EHPMK:<M

=B:F>M>KBGI:K:LM>KG:ELAHKM:QBLOB>P"B@NK>:G=KB@AMO>GMKB<NE:K;:L:E=B:F>M>KBGKB@AM O>GMKB<NE:K?H<NL>=:IB<:E<A:F;>KOB>P.B@AMO>GMKB<NE:K?NG<MBHGP:L:LL>LL>=NLBG@

?K:<MBHG:E:K>:<A:G@>=>KBO>=?KHFMA>>G==B:LMHEB<:G=>G=LRLMHEB<KB@AMO>GMKB<NE:K:K>:L F>:LNK>=BGKB@AMO>GMKB<NE:K?H<NL>=<A:F;>KOB>P"B@NK>,K>L>G<>H?:DBG>LB:

=RLDBG>LB::G=:G>NKRLFH?KB@AMO>GMKB<NE:K?K>>P:EEP:L:LL>LL>=JN:EBM:MBO>ERBG:EE

><AH<:K=BH@K:IAB<OB>PLKB@AMI:K:LM>KG:EOB>P EHG@I:K:LM>KG:EEHG@:G=LAHM:QBLOB>PL KB@AMO>GMKB<NE:K?H<NL>=<A:F;>KOB>P:G=LN;<HLM:EOB>P.B@AMO>GMKB<E>P:L:G:ERL>=

:<<HK=BG@MHLI><B?B<@NB=>EBG>L3>NL>=MA>IK>L>G<>H?K>@BHG:EP:EEFHMBHG

:;GHKF:EBMR KB@AMO>GMKB<NE:KHNM?EHPMK:<M=B:F>M>K:G=?K:<MBHG:E:K>:<A:G@>MH=>?BG>

LMKN<MNK:E:G=?NG<MBHG:E:;GHKF:EBMB>L<KBM>KB:

%G,:I>K P>K>IHKM>=E>?MO>GMKB<NE:K?NG<MBHG;R>C><MBHG?K:<MBHGF>:LNK>=NLBG@

/BFILHG]L;BIE:G>F>MAH=3>:LL>LL>=E>?MO>GMKB<NE:K@EH;:EEHG@BMN=BG:ELMK:BG:G=E>?M O>GMKB<NE:KF><A:GB<:E=BLI>KLBHG;RLI><DE>MK:<DBG@BF:@BG@(>?MO>GMKB<NE:K@EH;:E EHG@BMN=BG:ELMK:BGP:L=>?BG>=:L:O>K:@>I>:DLRLMHEB<LMK:BG:G=F><A:GB<:E=BLI>KLBHG:L MA>LM:G=:K==>OB:MBHGH?MA>MBF>?KHFHGL>MH?-./MHI>:DG>@:MBO>LMK:BG?KHF:EEE>?M O>GMKB<NE:KL>@F>GML

%G,:I>K I:K:LM>KG:EEHG@:QBLOB>P:G=:IB<:E<A:F;>KOB>PLP>K>BGLI><M>=?HK MA>IK>L>G<>H?) ) P:L=>?BG>=:L:=BLM:G<>H?≥FF?KHFFBMK:E:GGNENLE>?M :MKBNFCNG<MBHGMHMA>MHIH?E>?MO>GMKB<NE:KFRH<:K=BNF:M>G=LRLMHE>,HLM>KHE:M>K:E)

=BLM:G<>P:LF>:LNK>=BGI:K:LM>KG:EEHG@:QBLOB>P:M>G=LRLMHE>?KHFMA>MHIH?MA>;:L:E IHLM>KHE:M>K:EE>?MO>GMKB<NE:KP:EEMHMA>IHLM>KBHKFBMK:EE>:?E>ME>?M:MKBNFCNG<MBHG:G=

(34)

:GM>KHE:M>K:E) =BLM:G<>P:LF>:LNK>=BG:IB<:E<A:F;>KOB>P:M>G=LRLMHE>?KHFMA>

MHIH?MA>;:L:E:GM>KHE:M>K:EE>?MO>GMKB<NE:KP:EEMH:GM>KBHKIHLM>KBHKFBMK:EE>:?E>ME>?M :MKBNFCNG<MBHG"B@NK>) P:L<HKK><M>=?HK;H=RLNK?:<>:K>:)BMK:EO:EO>IKHE:IL>

P:L=>?BG>=:L:LNI>KBHK=BLIE:<>F>GMH?≥FFH?:GRI:KMH?FBMK:EE>:?E>M?KHFMA>FBMK:E :GGNENL:M>G=LRLMHE>BGI:K:LM>KG:EEHG@:QBLOB>PLMA>GHKF:EL:==E>LA:I>H?MA>FBMK:E O:EO><:G@BO>:?:EL>BFIK>LLBHGH?IKHE:IL> :IB<:E<A:F;>KOB>PP:LGHMNL>=MH=>?BG>

FBMK:EO:EO>IKHE:IL>3>F>:LNK>=:GM>KHIHLM>KBHKFBMK:E:GGNENL=B:F>M>K:M>G=LRLMHE>

:G=FB==B:LMHE>BGI:K:LM>KG:EEHG@:QBLOB>P BE:M>=FBMK:E:GGNENLP:L=>?BG>=:L:G :GM>KHIHLM>KBHK=B:F>M>KFFMAKHN@AHNMMA>>GMBK><:K=B:<<R<E>BG:=NEML-N:GMB?B<:MBHG H?FBMK:EK>@NK@BM:MBHGP:LI>K?HKF>=:<<HK=BG@MH@NB=>EBG>L

53A>1/4;/->05;3>-9;2<-@51:@?C5@4 ->2-:?E:0>;91-:0<-@51:@?C5@4;1E?51@F?E:0>;91C5@495@>-8-::A8A?

05?6A:/@5;:C5@4-:0C5@4;A@95@>-8B-8B1<>;8-<?1'(43+$1"3$2!+30$!02!0#(.4!1",!&(-&#.( $')"()$!!

(2'/$0,(11(.-

(35)

HKMB<KHHM=B:F>M>KP:LF>:LNK>=:MLBGNL>LH?2:EL:EO:BG=B:LMHE>?KHFE>:=BG@

>=@>MHE>:=BG@>=@>BG:=NEML:G=BGLRLMHE>?KHFBGG>K>=@>MHBGG>K>=@>BGI:MB>GML R>:KLHKMB<KHHM6L<HK>P:L<:E<NE:M>=NLBG@MA>HGEBG><:E<NE:MHK?HNG=HG):K?:G

?HNG=:MBHGP>;LBM>AMMILPPPF:K?:GHK@=QSL<HK>

(>?MO>GMKB<NE:KOHENF>LP>K>H;M:BG>=BG EHHILBG:G=<A:F;>KOB>PL:G=

NL>=MH<:E<NE:M>=E>?MO>GMKB<E>>C><MBHG?K:<MBHGNLBG@/BFILHG]LF>MAH=3>F>:LNK>=I>:D LRLMHEB<L>IM:EFBMK:E:GGNE:KO>EH<BMRL>IM:E/:G=I>:DLRLMHEB<E:M>K:EFBMK:E:GGNE:K O>EH<BMRE:M>K:E/;RINEL>P:O>MBLLN> HIIE>K)>:LNK>F>GMLP>K>=>KBO>=?KHF:IB<:E

<A:F;>KOB>P3>:LL>LL>=MK:GLFBMK:E?EHPO>EH<BMB>L!P:O>:G=P:O>:G=>:KERL>IM:E :G=E:M>K:EFBMK:E:GGNE:KI>:D=B:LMHEB<MBLLN> HIIE>KO>EH<BMB>LL>IM:E>]:G=E:M>K:E>];R INEL>P:O>BG<A:F;>KOB>P3>K>IHKM>=MKB<NLIB=K>@NK@BM:MBHGO>EH<BMR:G=E>?M:MKB:E OHENF>BG=>Q>=MH;H=RLNK?:<>:K>:<HFIE>M>=B:LMHEB<?NG<MBHG:LL>LLF>GMP:L I>K?HKF>=:<<HK=BG@MHMA>=B:@GHLMB<:E@HKBMAFH?E>?MO>GMKB<NE:K=B:LMHEB<=RL?NG<MBHG :<<HK=BG@MH!2%/!@NB=>EBG>L

:K=B:<F:@G>MB<K>LHG:G<>

:K=B:<F:@G>MB<K>LHG:G<>P:LI>K?HKF>=HG<EBGB<:EBG=B<:MBHGHG0L<:GG>K ):@G>MHG/HG:M: 2BLBHG,ENLHKO:GMH/B>F>GL !KE:G@>G #>KF:GRBG,:I>K,K>L>G<>

H?K>@BHG:E:DBG>LB: =RLDBG>LB::G==RLLRG<AKHGHNL<HGMK:<MBHGH?KB@AMO>GMKB<NE:K?K>>P:EE P:L:LL>LL>=JN:EBM:MBO>ER.B@AMO>GMKB<NE:KOHENF>LP:LF>:LNK>=L>FB:NMHF:MB<:EER:G=

KB@AMO>GMKB<NE:K>C><MBHG?K:<MBHGP:L<:E<NE:M>=?KHF>G==B:LMHEB<:G=>G=LRLMHEB<

OHENF>L,K>L>G<>H?LMKN<MNK:E:G=HK?NG<MBHG:E:;GHKF:EBMB>L:M<:K=B:<F:@G>MB<

K>LHG:G<>P:L=>?BG>=BGMA>IK>L>G<>H?K>@BHG:EP:EEFHMBHG:;GHKF:EBMB>L:LLH<B:M>=PBMA :=BE:M>=KB@AMO>GMKB<E>=>?BG>=:L:G>G==B:LMHEB<OHENF>≥FEFBGF:E>L:G=

(36)

≥FEFBG?>F:E>LHK=RL?NG<MBHG:EKB@AMO>GMKB<E>=>?BG>=;R:KB@AMO>GMKB<E>>C><MBHG

?K:<MBHGaHMABG<ENLBHG:G=?HEEHPNI>Q:FBG:MBHGLP>K>:G:ERL>=PA>G:O:BE:;E>

! "

L<>G=BG@:HKMB<:G>NKRLFLNK@>KRP:LI>K?HKF>=:<<HK=BG@MHK><HFF>G=:MBHGL :HKMB<KHHM=BE:M:MBHG≥<FHK:HKMB<KHHM=B:F>M>K≥<FBGMA>IK>L>G<>H?:==BMBHG:E KBLD?:<MHKLBG)"/:G=:HKMB<KHHM≥<FHKLF:EE>KBGMA>IK>L>G<>H?K:IB=ER

>QI:G=BG@:HKMB<KHHMBG:=NEML:G=BGMA>IK>L>G<>H??:FBERABLMHKRH?:@@K>LLBO>:HKMB<

=BL>:L>BGI:MB>GMLR>:KLHE=BG( /3>I>K?HKF>=MAHK:<H:;=HFBG:E:G=

=>L<>G=BG@:HKMB<:G>NKRLFLNK@>KR?HK:G:HKMB<=BE:M:MBHG≥<FBG)"/:G=≥<F BG( /3A>G:HKMB<LNK@>KRP:LI>K?HKF>=HGFBMK:EBG=B<:MBHG MA>I:MB>GMP:L

<>GLHK>=?HK:HKMB<>O>GM:MMA>MBF>H?LNK@>KR

)BMK:EO:EO>K>I:BKHKK>IE:<>F>GMP:LI>K?HKF>=BGI:MB>GMLPBMAA>FH=RG:FB<:EER LB@GB?B<:GMFBMK:EK>@NK@BM:MBHG;>?HK>HK:?M>K:HKMB<LNK@>KR3A>GFBMK:EO:EO>LNK@>KRP:L I>K?HKF>=<HG<HFBM:GMERPBMA:HKMB<LNK@>KR :HKMB<=BL>:L>FB@AMA:O>;>>GMA>IKBF:KBER BG=B<:MBHG?HKLNK@>KR

#

0A>LM:MBLMB<:E:G:ERLBLP:LI>K?HKF>=NLBG@/,//O/,//%G< AB<:@H %(

1/:G=/M:M:/!/M:M:HKI(( 04 1/0PHLB=>=IO:EN>L P>K><HGLB=>K>=LM:MBLMB<:EERLB@GB?B<:GM

:M>@HKB<:EO:KB:;E>LP>K>>QIK>LL>=BGGNF;>KLI>K<>GM:@>LHFI:KBLHGH?

<:M>@HKB<:EO:KB:;E>LP:LI>K?HKF>=;RABLJN:K>M>LMHK"BLA>K]L>Q:<MM>LM:L:IIKHIKB:M>

HGMBGNHNLO:KB:;E>LP>K>>QIK>LL>=:LF>:GLM:G=:K==>OB:MBHG7/ 8HKF>=B:G7%-.8

(37)

HFI:KBLHGH?<HGMBGNHNLO:KB:;E>LP:LI>K?HKF>=NLBG@/MN=>GMgL0M>LMB?GHKF:EER

=BLMKB;NM>=HK):GG3ABMG>R1GHGI:K:F>MKB<M>LMB?GHM

%GMK::G=BGM>KH;L>KO>KO:KB:;BEBMRP:L:LL>LL>=?HK<HGO>GMBHG:E><AH<:K=BH@K:IAB<

I:K:F>M>KLKB@AMO>GMKB<NE:KHNM?EHPMK:<M=B:F>M>K KB@AMO>GMKB<NE:K;:L:E=B:F>M>K KB@AM O>GMKB<NE:K?K:<MBHG:E:K>:<A:G@>:G=E>?MO>GMKB<NE:K@EH;:EEHG@BMN=BG:ELMK:BG,:I>K KB@AMO>GMKB<NE:KHNM?EHPMK:<M=B:F>M>K,:I>K:G=LRLMHEB<:G==B:LMHEB<FBMK:E:GGNENL

=B:F>M>KL:G=IHLM>KHE:M>K:E) =BLM:G<>,:I>K

,:I>K

!<AH<:K=BH@K:IAB<I:K:F>M>KLP>K><HFI:K>=;>MP>>GIKH;:G=L:G=?:FBERF>F;>KL :MBG<ENLBHG:G=E:LM?HEEHPNI:G=MA>L:F>I:K:F>M>KLP>K>:ELH<HFI:K>=;>MP>>G

BG<ENLBHG:G=E:LM?HEEHPNIBGMA>@KHNIH?IKH;:G=L:G=BG?:FBERF>F;>KLL>I:K:M>ER;R MPHL:FIE>0M>LM

.>I>:M>=F>:LNK>F>GMLH?><AH<:K=BH@K:IAB<I:K:F>M>KL=NKBG@?HEEHPNIP>K>

BGMKH=N<>=BG:EBG>:KFBQ>=FH=>E:G:ERLBLPBMA>Q<A:G@>:;E><HO:KB:G<>LMKN<MNK>:G=

K:G=HFBGM>K<>IM3>NL>=:GBGM>K:<MBHGM>KF;>MP>>GIKH;:G=LM:MNL:G=?HEEHPNIMBF>BG HK=>KMHMK:<>LMKN<MNK:E:G=?NG<MBHG:EI:K:F>M>KL>OHENMBHGHO>KMBF>:G=<HFI:K>MA>

<A:G@>H?MA>L>I:K:F>M>KL;>MP>>G?:FBERF>F;>KL:G=IKH;:G=L

0A>IK>=B<MBO>G:MNK>H?=BL>:L>IKH@K>LLBHG?HKBG<B=>GML>O>K>O>GMKB<NE:K

:KKARMAFB<>O>GMLP:LM>LM>=BG:FNEMBO:KB:M>HQK>@K>LLBHG:G:ERLBL:=CNLM>=?HKIHLLB;E>

<HG?HNG=>KLBG<EN=BG@IKH;:G=LLM:MNL

(38)

,:I>K

3>>LMBF:M>=:G=<HFI:K>=LNKOBO:E?K>>H?L>O>K>O>GMKB<NE:K:KKARMAFB<>O>GMLBG K/I:MB>GMLPBMA:G=PBMAHNM=BE:M>=KB@AMO>GMKB<NE:KHNM?EHPMK:<M:G=PBMA:G=PBMAHNM IKHEHG@>=M>KFBG:E:<MBO:MBHG=NK:MBHGHG!#;R':IE:G)>B>KLNKOBO:E:G:ERLBL

0H=>M><MK/I:MB>GMLPBMAO>GMKB<NE:K:KKARMAFB:LP><HFI:K>=MA>=B??>K>GMB:MBHG

<:I:<BMRH?FH=>EL :IK>=B<MBHGFH=>E<HF;BGBG@MRI>!#I:MM>KG:G=LRG<HI>:G=:

L><HG=IK>=B<MBHGFH=>E<HF;BGBG@MRI>!#I:MM>KG LRG<HI>:G==BE:M>=KB@AMO>GMKB<NE:K HNM?EHPMK:<M NLBG@:K>:NG=>KMA>K><>BO>KHI>K:MBG@<NKO> ABLJN:K>:G=D:BD>

BG?HKF:MBHG<KBM>KBHG

,:I>K

3>>LMBF:M>=:@>:M:HKMB<>O>GM:G=FBMK:EO:EO>LNK@>KR:G=LNKOBO:E?K>>H?:HKMB<

>O>GML:G=H?FBMK:EO:EO>LNK@>KRBGI:MB>GMLPBMA:G=PBMAHNM) NLBG@':IE:G)>B>K LNKOBO:E:G:ERLBL

3>M>LM>=MA>:LLH<B:MBHG;>MP>>G) :G=><AH<:K=BH@K:IAB<I:K:F>M>KLE>?M O>GMKB<NE:K=BF>GLBHGL:G=?NG<MBHG:=CNLM>=?HKIHLLB;E><HG?HNG=>KLNLBG@FNEMBO:KB:M>

EBG>:KK>@K>LLBHG3>NL>=,>:KLHGgL:G:ERLBLMH>O:EN:M>MA><HKK>E:MBHG;>MP>>G)

=BLM:G<>:G=<A:K:<M>KBLMB<LH?FBMK:E:GGNENL

(39)

/MN=R:G=P>K>:IIKHO>=;R.>@BHG:EHFFBMM>>L?HK)>=B<:E:G=$>:EMA .>L>:K<A!MAB<L *HKP:R/:.!'/dK_LM /MN=R;RMA>!MAB<L

HFFBMM>>H?16KNLL>E:G=/MN=RP:L:IIKHO>=;RMA>%GLMBMNMBHG:E.>OB>P H:K=H?+LEH1GBO>KLBMR$HLIBM:E .BDLAHLIBM:E>M *HKP:R,2+

EELMN=B>L<HFIEB>=PBMAMA> ><E:K:MBHGH?$>ELBGDB,:KMB<BI:GML?KHF/MN=R:G=

@:O>PKBMM>GBG?HKF>=<HGL>GM/MN=RP:LK>MKHLI><MBO>:G=:EE<EBGB<:E=:M:P>K>

K>MKB>O>=?KHFI:MB>GML]>E><MKHGB<:EF>=B<:E?BE>L%GLMBMNMBHG:E.>OB>PH:K=P:BO>=

BG?HKF>=<HGL>GMBG/MN=R

,:I>K

+NK?BG=BG@LFB@AMBG=B<:M>MA:M<:KKRBG@:@>G>MB<FNM:MBHGBFIEB>L:G>@:MBO>

IKH@GHLBLPBMA:NGB?HKF=BL>:L><HNKL>$HP>O>K H?MA>A>:EMAR?:FBERF>F;>KL:M

@>G>MB<=B:@GHLBLK>F:BG>==BL>:L>?K>>:MMA>>G=H??HEEHPNI.>I>:M>=<EBGB<:E?HEEHPNIL FB@AM;>:ILR<AHEH@B<:E;NK=>G?HKBG=BOB=N:EL:MEHPKBLD

,:I>K

0RI>!#I:MM>KG:G=LRG<HI>:K>K><H@GBS>=KBLD?:<MHK?HK:KKARMAFB<>O>GMLBG K/0A>IK>L>G<>H?:=BE:M>=KB@AMO>GMKB<NE:KHNM?EHPMK:<MP:L=>L<KB;>=BGMA>L>AB@AKBLD I:MB>GML:G=FB@AMGHM;>BG=>I>G=>GMER:LLH<B:M>=PBMA:==BMBHG:EKBLD%G<ENLBHGH?:AB@A IKHIHKMBHGH?/*FNM:MBHGIHLBMBO>K/I:MB>GMLFB@AM>QIE:BG:AB@A>KKBLDIKH?BE>PBMA AB@AIK>O:E>G<>H?LMKN<MNK:E:G=?NG<MBHG:E:;GHKF:EBMB>LBGMABLLMN=RIHINE:MBHG

(40)

,:I>K

<:NL:EK>E:MBHG;>MP>>G=BLCNG<MBHGH?MA>:GGNENL:G=FBMK:EO:EO>=>@>G>K:MBHG K>F:BGLARIHMA>MB<:EBGI:MB>GMLPBMA)"/:G=( /PAH:K>:EK>:=R@>G>MB<:EERIK>=BLIHL>=

MHFRQHF:MHNL=>@>G>K:MBHGH?MA>FBMK:EO:EO>,KH@GHLBLBL=HFBG:M>=;R:HKMB<I:MAHEH@R BGI:MB>GMLPBMA)"/:G=( /%MBLNGLNK>MA:M:<EHL>K?HEEHPNIBGMA>IK>L>G<>H?) :==BMBHG:EERBFIKHO>LIKH@GHLBL:G=HNMP>B@ALMA>ILR<AHEH@B<:E;NK=>G

(41)

"

3>BG<EN=>=I:MB>GMLPBMA:G=FNM:MBHGIHLBMBO>?:FBERF>F;>KL F:E>L :@>:MBG<ENLBHG`R>:KLHE= IKH;:G=L"B?MRHG>I>K<>GMH?IKH;:G=LP>K>

FNM:MBHGIHLBMBO>/MN=RI:KMB<BI:GMLP>K>?HEEHP>=?HKR>:KL%-.

$B@A=BL>:L>I>G>MK:G<>BG?:FBERF>F;>KL

M@>G>MB<=B:@GHLBL H?MA>?:FBERF>F;>KLA:=:EK>:=RLB@GLH?

=BL>:L>+?MA>A>:EMAR?:FBERF>F;>KL:MBG<ENLBHG =>O>EHI>=>E><MKB<:E:G=HK LMKN<MNK:E<KBM>KB:=NKBG@R>:KL%-.H??HEEHPNI

/BFBE:K=BL>:L>IKH@K>LLBHGBGIKH;:G=L:G=?:FBERF>F;>KL

,KH;:G=LA:=AB@A>KIK>O:E>G<>H?F:CHKLMKN<MNK:E<KBM>KB:0:;E> @K>:M>KKB@AM O>GMKB<NE:K=B:F>M>KL:G=PHKL>KB@AM:G=E>?M<:K=B:<?NG<MBHG0:;E>;HMA:MBG<ENLBHG:G=

:ME:LM?HEEHPNI$HP>O>K IK>O:E>G<>H?F:CHK><AH<:K=BH@K:IAB<LMKN<MNK:E<KBM>KB:

BG<K>:L>= KB@AMO>GMKB<E>LBS>BG<K>:L>=:G=KB@AM:G=E>?MO>GMKB<NE:K?NG<MBHG=>M>KBHK:M>=

=NKBG@?HEEHPNI;HMABGIKH;:G=L:G=?:FBERF>F;>KL"NKMA>KFHK> KB@AMO>GMKB<E>HNM?EHP MK:<M=B:F>M>K:G=KB@AMO>GMKB<NE:K;:L:E=B:F>M>K=BE:M>=:G=E>?MO>GMKB<NE:K@EH;:E

EHG@BMN=BG:ELMK:BGPHKL>G>=:M:LBFBE:KK:M>BGIKH;:G=L:G=?:FBERF>F;>KL0:;E>

"B@NK>%GM>K>LMBG@ER IKH@K>LLBHGK:M>H?KB@AMO>GMKB<NE:K?K:<MBHG:E:K>:<A:G@>P:L>O>G AB@A>KBG?:FBERF>F;>KLMA:GBMP:LBGIKH;:G=L0:;E> "B@NK>3>?HNG=LBFBE:K LMKN<MNK:EIKH@K>LLBHGBGI:MB>GMLPBMA:G=PBMAHNMBGBMB:ELMKN<MNK:E:;GHKF:EBMB>L AB@A>KK:M>

H?=>M>KBHK:MBHGH?E>?MO>GMKB<NE:K?NG<MBHGBG /, /#FNM:MBHG<:KKB>KL:G=AB@A>KK:M>H?

=>M>KBHK:MBHGH?KB@AMO>GMKB<NE:K?NG<MBHGBG,',FNM:MBHGIHLBMBO>I:MB>GML

(42)

'-.81&@>A/@A>-8/>5@1>5--//;>05:3@; %1B5?10'-?7;>/1/;:?1:?A?-@5:/8A?5;:-:0-@2;88;CA<5:<-@51:@?C5@4 ->>4E@49;31:5//->05;9E;<-@4E-:09A@-@5;:<;[email protected]>?

:/8@>5;:

:

;88;B@<

:

%

"-6;=/=5?1=5-

/4;/->05;3>-<4E:

'135;:-8'*-75:1>5-0D>75:1>5-;=-:1@=D>9-:0'*$)<8-C≥99(/;==1/?10≥99 9;='*$)<>-C≥99 (/;==1/?10≥99 991->@=10-?1:005->?;81;=≤

%=;.-:0>:

-958D919.1=>:

%

%/>5@1>5-:

'135;:-8'*-75:1>5-;=0D>75:1>5-;=0D>>D:/4=;:;@>'*/;:?=-/?5;:-:0'*1:005->?;85/A;8@91 (≥98 99-81;=≥

98 9219-81;='*161/?5;:2=-/?5;:≤

%=;.-:0>:

-958D919.1=>:

%

"5:;=/=5?1=5-

/4;/->05;3>-<4E:

'135;:-8'*-75:1>5-;=0D>75:1>5-;=0D>>D:/4=;:;@>'*/;:?=-/?5;:-:0'*$)<8-C≥99?;99(/;==1/?10≥

99 9?;99 9;='*$)<>-C≥99?;99(/;==1/?10≥99 9?;99 991->@=10-?1:005->?;81

;=≤

%=;.-:0>:

-958D919.1=>:

%

%/>5@1>5-:

'135;:-8'*-75:1>5-;=0D>75:1>5-;=0D>>D:/4=;:;@>'*/;:?=-/?5;:-:0'*1:005->?;85/A;8@91 (≥?;98 99-81

;=≥?;98 9219-81;='*161/?5;:2=-/?5;:?;≤

%=;.-:0>:

-958D919.1=>:

%

)-8A1?->12>1=A1:/51?#B-8A1?->1/-8/[email protected] /!19->?@1?@;>45?=A->1@1?@-?-<<>;<>5-@1..>1B5-@5;:?&

.;0E?A>2-/1->1- %/->05-/9-3:1@5/>1?;:-:/12>-/@5;:-8->1-/4-:31<8-D<->-?@1>:-88;:3-D5?B51C<?-D

<->-?@1>:-8?4;>@-D5?B51C%)>534@B1:@>5/81%)"'%);A@28;C@>-/@ %C-?<1>2;>9105:<-@51:@?-@5:/8A?5;:-:0 5:<-@51:@?-@8-?@2;88;CA<

(43)

'-.81&@>A/@A>-8<>;3>1??5;:.E1/4;/->05;3>-<45/-??1??91:@?-:0/->05-/9-3:1@5/>1?;:-:/1-??1??91:@?5:

<-@51:@?C5@4->>4E@49;31:5//->05;9E;<-@4E-:09A@-@5;:<;[email protected]>?

:/8@>5;:

:

%=;3=1>>5;:

=-?1 D1-=(

;88;B@<

:

%2;=<=;3=1>>5;:

/4;/-=05;3=-<4D

)

%=;.-:0>: ± ±

-958D919.1=>: ± ±

%2;=5:?1=-/?5;:

%2;=/;9<-=5>;:

)&

%=;.-:0>: F F

-958D919.1=>: F F

%2;=5:?1=-/?5;:

%2;=/;9<-=5>;:

%)

%=;.-:0>: F F

-958D919.1=>: F F

%2;=5:?1=-/?5;:

%2;=/;9<-=5>;:

%)"'99

%=;.-:0>: F F

-958D919.1=>: F F

%2;=5:?1=-/?5;:

%2;=/;9<-=5>;:

%)99

Referanser

RELATERTE DOKUMENTER