• Aucun résultat trouvé

Male-specific colon motility dysfunction in the TashT mouse line

N/A
N/A
Protected

Academic year: 2021

Partager "Male-specific colon motility dysfunction in the TashT mouse line"

Copied!
43
0
0

Texte intégral

(1)Neurogastroenterology and Motility. .   .   0DOHVSHFLILFFRORQPRWLOLW\G\VIXQFWLRQLQWKH7DVK7PRXVH OLQH.   -RXUQDO 1HXURJDVWURHQWHURORJ\DQG0RWLOLW\. r ee rP Fo. 0DQXVFULSW,' 1025 0DQXVFULSW7\SH 2ULJLQDO$UWLFOH 'DWH6XEPLWWHGE\WKH$XWKRU QD. &RPSOHWH/LVWRI$XWKRUV 7RXUp$ERXEDFULQH8QLYHUVLWHGX4XHEHFD0RQWUHDO6FLHQFHVELRORJLTXHV &KDUULHU%DSWLVWH8QLYHUVLWHGX4XHEHFD0RQWUHDO6FLHQFHVELRORJLTXHV 3LORQ1LFRODV8QLYHUVLWHGX4XHEHFD0RQWUHDO6FLHQFHVELRORJLTXHV .H\:RUGV. . . ew vi Re. . &KURQLFFRQVWLSDWLRQ(QWHULFQHUYRXVV\VWHP+LUVFKVSUXQJ VGLVHDVH 0\HQWHULFSOH[XV.

(2) Page 1 of 42. dŽƵƌĠϭ . 0DOHVSHFLILFFRORQPRWLOLW\G\VIXQFWLRQLQWKH7DVK7PRXVHOLQH  $ERXEDFULQH0DKDPDQH7RXUp%DSWLVWH&KDUULHUDQG1LFRODV3LORQ . 0ROHFXODU *HQHWLFV RI 'HYHORSPHQW /DERUDWRU\ 'HSDUWPHQW RI %LRORJLFDO 6FLHQFHV DQG %LR0HG 5HVHDUFK&HQWHU)DFXOW\RI6FLHQFHV8QLYHUVLW\RI4XHEHFDW0RQWUHDO 84$0

(3) 0RQWUHDO&DQDGD . r ee rP Fo. . &RUUHVSRQGHQFHWR1LFRODV3LORQ'HSDUWPHQWRI%LRORJLFDO6FLHQFHVDQG%LR0HG5HVHDUFK&HQWHU )DFXOW\ RI 6FLHQFHV 8QLYHUVLW\ RI 4XHEHF DW 0RQWUHDO 84$0

(4)   3UHVLGHQW.HQQHG\ $YH 0RQWUHDO 34 &DQDGD +; < 7HO  [ )D[  (PDLO SLORQQLFRODV#XTDPFD   .(<0(66$*(6. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility. x ,QWKH7DVK7PRXVHPRGHORI+LUVFKVSUXQJGLVHDVHDQLPSRUWDQWVXEVHWRIKRPR]\JRXV DQLPDOVGRQRWGHYHORSDJDQJOLRQLFPHJDFRORQGHVSLWHKDYLQJGLVWDOFRORQDJDQJOLRQRVLVDQGRU K\SRJDQJOLRQRVLV. x %RWKGLVWDOFRORQDJDQJOLRQRVLVDQGK\SRJDQJOLRQRVLVDUHPRUHVHYHUHLQ7DVK77J7JPDOHV x 7DVK77J7JPDOHVEXWQRWIHPDOHVGLVSOD\DOWHUHGGLVWDOFRORQLFPRWLOLW\LQGHSHQGHQWO\RI DJDQJOLRQRVLV x $QLQFUHDVHRIQLWUHUJLFQHXURQVWKDWLVUHVWULFWHGWRWKHPRVWGLVWDOJDQJOLRQDWHGUHJLRQVLVDOVR REVHUYHGLQ7DVK77J7JPDOHVEXWQRWLQIHPDOHV .

(5) Neurogastroenterology and Motility. dŽƵƌĠϮ . $%675$&7 %DFNJURXQG ,Q +LUVFKVSUXQJ GLVHDVH +6&5

(6)  WKH DEVHQFH RI P\HQWHULF QHXUDO JDQJOLD LQ WKH GLVWDO ERZHO SUHYHQWV PRWLOLW\ DQG WKHUHE\ FDXVHV IXQFWLRQDO LQWHVWLQDO REVWUXFWLRQ $OWKRXJK VXUJLFDO UHVHFWLRQ RI WKH DJDQJOLRQLF VHJPHQW DOORZV +6&5 FKLOGUHQ WR VXUYLYH WKLV FRQGLWLRQ D QXPEHU RI SDWLHQWVVWLOOVXIIHUIURPLPSDLUHGPRWLOLW\GHVSLWHKDYLQJP\HQWHULFJDQJOLDLQWKHLUSRVWRSHUDWLYHGLVWDO ERZHO6XFKSKHQRPHQRQLVDOVRREVHUYHGLQSDWLHQWVVXIIHULQJIURPRWKHUHQWHULFQHXURSDWKLHVDQGLQ ERWK FDVHV FRORQLF G\VPRWLOLW\ LV EHOLHYHG WR UHVXOW IURP DEQRUPDOLWLHV RI P\HQWHULF JDQJOLD DQGRU. r ee rP Fo. DVVRFLDWHG LQWHUVWLWLDO FHOOV RI &DMDO ,&&

(7)  7R EHWWHU XQGHUVWDQG WKLV ZH XVHG D UHFHQWO\ GHVFULEHG +6&5PRXVHPRGHOFDOOHG7DVK7. 0HWKRGV ,QWHVWLQDO PRWLOLW\ SDUDPHWHUV ZHUH DVVHVVHG DQG FRUUHODWHG ZLWK H[WHQW RI DJDQJOLRQRVLV DV ZHOODVZLWKQHXURQDOGHQVLW\LQJDQJOLRQDWHGUHJLRQV7KHQHXUDOFRPSRVLWLRQRIWKHP\HQWHULFSOH[XV DVZHOODVWKHVWDWXVRI,&&QHWZRUNVZDVDOVRHYDOXDWHGXVLQJLPPXQRIOXRUHVFHQFH .H\5HVXOWV7DVK77J7JPLFHGLVSOD\DVWURQJPDOHELDVLQWKHVHYHULW\RIERWKFRORQLFDJDQJOLRQRVLV. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 2 of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

(8) Page 3 of 42. dŽƵƌĠϯ . ,1752'8&7,21 7KH QHXUDO FUHVWGHULYHG HQWHULF QHUYRXV V\VWHP (16

(9)  LV WKH LQWULQVLF QHXUDO QHWZRUN RI WKH HQWLUH JDVWURLQWHVWLQDO *,

(10) WUDFW%XULHGZLWKLQWKHJXWZDOOWKH(16LVPDLQO\RUJDQL]HGLQWRWZRPDMRU LQWHUFRQQHFWHG SOH[XVHV WKH P\HQWHULF $XHUEDFK V

(11)  SOH[XV DQG WKH VXEPXFRVDO 0HLVVQHU V

(12)  SOH[XV (DFK SOH[XV FRQVLVWV RI LQWHUFRQQHFWHG JDQJOLD FRQWDLQLQJ QHXURQV DQG DVVRFLDWHG JOLD :KLOH WKH P\HQWHULFSOH[XVQRWDEO\FRQWUROVLQWHVWLQDOPRWLOLW\LQFROODERUDWLRQZLWKWKHLQWHUVWLWLDOFHOOVRI&DMDO ,&&

(13) ±WKHSDFHPDNHUFHOOVRIWKHERZHOWKHVXEPXFRVDOSOH[XVUHJXODWHVVHYHUDOPXFRVDOIXQFWLRQV. r ee rP Fo. 7R SHUIRUP WKHVH WDVNV HDFK SOH[XV PXVW FRQWDLQ DSSURSULDWH GHQVLW\ RI JDQJOLD DV ZHOO DV DGHTXDWH SURSRUWLRQVRIQHXURQVXEW\SHVDQGJOLDOFHOOVZLWKLQHDFKJDQJOLRQ . )DLOXUH RI QHXUDO FUHVWGHULYHG (16 SURJHQLWRUV WR SURSHUO\ UHDFK WKH GLVWDO ERZHO GXULQJ SUHQDWDO GHYHORSPHQWPD\FDXVH+LUVFKVSUXQJGLVHDVH +6&5

(14) ZKLFKDIIHFWVRQHLQOLYHELUWKVZLWKD PDOHWRIHPDOHUDWLR+6&5LVDOLIHWKUHDWHQLQJFRQGLWLRQFKDUDFWHUL]HGE\IXQFWLRQDOREVWUXFWLRQLQ. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility. WKHGLVWDOERZHOGXHWRWKHODFNRIHQWHULFQHXUDOJDQJOLD DJDQJOLRQRVLV

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

(16) Neurogastroenterology and Motility. dŽƵƌĠϰ . $QLPDOV IURP +6&5 PRXVH OLQHV ZLWK PLOG SKHQRW\SLF SUHVHQWDWLRQ HJ K\SRJDQJOLRQRVLV DQGRU XOWUDVKRUW VHJPHQW DJDQJOLRQRVLV

(17)  WKDW GR QRW WULJJHU IXQFWLRQDO LQWHVWLQDO REVWUXFWLRQ KDYH SURYHQ HVSHFLDOO\XVHIXOIRUHYDOXDWLQJWKHFRQWULEXWLRQRIUHODWLYHO\PRGHVW(16GHIHFWVWRGHILFLWVLQERZHO PRWLOLW\ $OWKRXJK JHQGHU GLIIHUHQFHV LQ WKH SHQHWUDQFH DQGRU VHYHULW\ RI WKH DERYH SKHQRW\SHV KDYH EHHQ VXVSHFWHG LQIRUPDWLRQ UHJDUGLQJ WKH UHODWLRQVKLS EHWZHHQ D JLYHQ (16 GHIHFW VWUXFWXUDO DEQRUPDOLWLHVRUQHXUDOLPEDODQFH

(18) DQG*,G\VPRWLOLW\LQDVH[VSHFLILFPDQQHULVYHU\VFDUFH . r ee rP Fo. :HUHFHQWO\UHSRUWHGWKHJHQHUDWLRQRIDQLQVHUWLRQDOPXWDQWPRXVHOLQHFDOOHG7DVK7LQZKLFKDURXQG  RI KRPR]\JRWHV 7DVK77J7J

(19)  VXFFXPE WR DJDQJOLRQLF PHJDFRORQ DURXQG ZHDQLQJ DJH ZLWK D VWULNLQJ  PDOH WR IHPDOH UDWLR /RFDWHG LQ D FKURPRVRPH  JHQH GHVHUW WKH 7DVK7 PXWDWLRQ SHUWXUEV WKH DFWLYLW\ RI VLOHQFHU HOHPHQWV WKDW DUH QRUPDOO\ LQYROYHG LQ WKH GLUHFW UHSUHVVLRQ RI WKH XQFKDUDFWHUL]HGJHQH)DPE±DQGSRWHQWLDOO\RWKHUJHQHV±LQQHXUDOFUHVWGHULYHG(16SURJHQLWRUV %\ D FXUUHQWO\ XQNQRZQ PHFKDQLVP WKH 7DVK7 PXWDWLRQ QRWDEO\ UHVXOWV LQ WKH GHUHJXODWLRQ RI NH\. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 4 of 42. VLJQDOLQJ SDWKZD\V IRU (16 GHYHORSPHQW *GQI5HW DQG (GQ(GQUE

(20)  DQG FRQVHTXHQWO\ WR VORZHU PLJUDWLRQRIQHXUDOFUHVWGHULYHG(16SURJHQLWRUVLQHPEU\RQLFLQWHVWLQHV:KDWH[DFWO\H[SODLQVWKH VH[ELDVLQPHJDFRORQH[SUHVVLYLW\DWWKHPROHFXODUOHYHOLVDOVRFXUUHQWO\XQNQRZQ+RZHYHUDWWKH KLVWRORJLFDOOHYHOZHIRXQGWKDWLWFDQEHH[SODLQHGE\WKHIDFWWKDWWKHFRORQRIPDOHVLVJDQJOLRQDWHG RQDYHUDJHDURXQGDWKUHVKROGOHYHORIPLQLPDOFRORQLFLQQHUYDWLRQIRU)9%1DQLPDOV aRIWRWDO FRORQOHQJWK

(21) ZKLOHWKHFRORQRIIHPDOHVLVJDQJOLRQDWHGRQDYHUDJHMXVWEH\RQGWKLVSRLQW  ,Q WKLV VWXG\ ZH QRZ UHSRUW WKDW DGXOW 7DVK77J7J PLFH WKDW GR QRW GHYHORS DJDQJOLRQLF PHJDFRORQ VXIIHU IURP FKURQLF FRQVWLSDWLRQ LQ D PDOHVSHFLILF PDQQHU ([WHQVLYH FKDUDFWHUL]DWLRQ RI *, PRWLOLW\ DQG P\HQWHULF SOH[XV VWUXFWXUHFRPSRVLWLRQ VXJJHVWV WKDW WKLV LV GXH WR DJDQJOLRQRVLV DQGRU.

(22) Page 5 of 42. dŽƵƌĠϱ . K\SRJDQJOLRQRVLVFRPELQHGZLWKPDOHVSHFLILFQHXURQDOVXEW\SHVLPEDODQFHLQWKHJDQJOLRQDWHGGLVWDO FRORQ. . r ee rP Fo ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility.

(23) Neurogastroenterology and Motility. dŽƵƌĠϲ . 0$7(5,$/6$1'0(7+2'6 $QLPDOV $OO DQLPDO VWXGLHV ZHUH FRQGXFWHG LQ DFFRUGDQFH ZLWK WKH JXLGHOLQHV RI WKH &DQDGLDQ &RXQFLO RQ $QLPDO &DUH &&$&

(24)  DQG DSSURYHG E\ WKH UHOHYDQW LQVWLWXWLRQDO FRPPLWWHH &RPLWp LQVWLWXWLRQQHO GH SURWHFWLRQ GHV DQLPDX[ &,3$ UHIHUHQFH 

(25)  RI 8QLYHUVLW\ RI 4XHEHF DW 0RQWUHDO 84$0

(26)  %RWK PXWDQW 7DVK77J7J

(27) DQGZLOGW\SHDQLPDOVDUHRIWKHVDPHJHQHWLFEDFNJURXQG )9%1

(28) $OOVWXGLHV ZHUHSHUIRUPHGXVLQJYLUJLQPLFHEHWZHHQPRQWKVRIDJHZLWKWKHH[FHSWLRQWKDWERG\ZHLJKWZDV. r ee rP Fo. DOVRGHWHUPLQHGIRUSRVWQDWDOGD\ 3

(29) DQGPLFH. %RG\ZHLJKWZDVDVVHVVHGLQWKHPRUQLQJXVLQJDKLJKSUHFLVLRQGLJLWDOVFDOH .LORWHFK.+$

(30) )RU WLVVXHSUHSDUDWLRQPLFHZHUHHXWKDQL]HGIROORZLQJLVRIOXUDQHDQHVWKHVLDDQGUHOHYDQWERZHOVHJPHQWV GXRGHQXP DQG FRORQ

(31)  ZHUH LPPHGLDWHO\ GLVVHFWHG RXW FXW ORQJLWXGLQDOO\ DORQJ WKH PHVHQWHU\ DQG SLQQHG VHURVDO VLGH GRZQ RQ DJDUFRDWHG GLVKHV LQ SKRVSKDWH EXIIHU VDOLQH 3%6

(32)  7KH WLVVXHV ZHUH IL[HGRYHUQLJKWDWž&LQDVROXWLRQFRQWDLQLQJSKRVSKDWHEXIIHUHGSDUDIRUPDOGHK\GH 3)$

(33) $IWHU. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 6 of 42. UHPRYDORIWKHPXFRVDVXEPXFRVDOD\HUVPXVFOHVWULSVZHUHWKHQGHK\GUDWHGLQPHWKDQRODQGVWRUHDW ž&XQWLOODEHOOLQJ7KHSRVLWLRQRIDOOERZHOVXEUHJLRQVXVHGLQWKLVVWXG\LVGHSLFWHGLQ6XSSOHPHQWDO )LJXUH 6WDLQLQJRIDFHW\OFKROLQHVWHUDVHDFWLYLW\. 7KH ZKROH FRORQ IURP FHFXP WR DQXV

(34)  ZDV FROOHFWHG DV DERYH DQG VWDLQHG IRU DFHW\OFKROLQHVWHUDVH $&K(

(35) DFWLYLW\HVVHQWLDOO\DVSUHYLRXVO\GHVFULEHG7KHOHQJWKRIWKHP\HQWHULFSOH[XVZDVPHDVXUHG ZLWK D PLOOLPHWHU UXOHU DQG WKHQ FRQYHUWHG LQWR SHUFHQWDJH RI WKH HQWLUH OHQJWK RI WKH FRORQ ,PDJHV ZHUH DFTXLUHG XVLQJ D ')& FDPHUD PRXQWHG RQ D 0)$ VWHUHRPLFURVFRSH /HLFD PLFURV\VWHPV

(36) 7RHYDOXDWHP\HQWHULFSOH[XVGHQVLW\LPDJHVZHUHFDSWXUHGDW;PDJQLILFDWLRQIURP WKHSUR[LPDOPLGDQGGLVWDOPLGFRORQ 0&

(37) DVZHOODVIURPWKHSUR[LPDODQGPLGGLVWDOFRORQ '&

(38)  RQHUHSUHVHQWDWLYHLPDJHSHUUHJLRQ

(39) )RUHDFKRIWKHVHVXEUHJLRQVWLVVXHZLGWKZDVDOVRGHWHUPLQHG.

(40) Page 7 of 42. dŽƵƌĠϳ . XVLQJDPLOOLPHWHUUXOHU)RUHDFKLPDJHWKHDUHDRFFXSLHGE\WKHP\HQWHULFSOH[XVZDVPHDVXUHGLQD UHSUHVHQWDWLYH ILHOG RI YLHZ FRUUHVSRQGLQJ WR D VTXDUH RI IL[HG GLPHQVLRQ PP

(41)  XVLQJ WKH ,PDJH $GMXVW7KUHVKROG&RORU

(42) DQG$QDO\]H 0HDVXUH

(43) IXQFWLRQVRI,PDJH-0\HQWHULFSOH[XVGHQVLW\ZDV H[SUHVVHGLQSHUFHQWDJH RIWKHWRWDODUHDRIWKHILHOGRIYLHZ5HVXOWV IRU ZKROH0&DQG'&UHJLRQV ZHUHREWDLQHGE\DYHUDJLQJWKHGDWDRIWKHUHVSHFWLYHVXEUHJLRQV ,PPXQRIOXRUHVFHQFH 'HK\GUDWHG PXVFOH VWULSV IURP WKH GXRGHQXP SUR[LPDO 0& SUR[LPDO '& DQG PLG '& ZHUH. r ee rP Fo. UHK\GUDWHGDQGLQFXEDWHGKRXUVDWURRPWHPSHUDWXUHLQEORFNLQJVROXWLRQ IHWDOERYLQHVHUXP 7ULWRQ;LQ3%6

(44) 7LVVXHVZHUHLQFXEDWHGZLWKSULPDU\DQWLERGLHVRYHUQLJKWDWƒ&DQGZLWK UHOHYDQWVHFRQGDU\DQWLERGLHVIRUKRXUVDWURRPWHPSHUDWXUH(DFKDQWLERG\ZDVGLOXWHGLQEORFNLQJ VROXWLRQ GLOXWLRQ IDFWRU DQG RWKHU DQWLERG\ GHWDLOV FDQ EH IRXQG LQ 6XSSOHPHQWDO 7DEOH 

(45)  0XVFOHV VWULSV IURP WKH GXRGHQXP SUR[LPDO 0& DQG PLG '& ZHUH XVHG IRU +X&'  Q1RV DQG +X&'  &DOUHWLQLQ FRODEHOOLQJV 7KRVH IURP SUR[LPDO DQG PLG '& DV ZHOO IURP GLVWDO '& ZHUH XVHG IRU. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility. +X&'  6R[ DQG ȕ,,,7XEXOLQ  F.LW FRODEHOOLQJV UHVSHFWLYHO\ )RU HDFK ERZHO VHJPHQW —P WKLFN VWDFNV RI  ILHOGV RI YLHZ FRUUHVSRQGLQJ WR D VTXDUH RI IL[HG GLPHQVLRQ PP

(46)  ZHUH UDQGRPO\FDSWXUHGZLWKWKH;REMHFWLYHRID1LNRQ$FRQIRFDOXQLW UXQZLWKWKH1,6(OHPHQW$5 VRIWZDUH

(47) XVLQJVWDQGDUGH[FLWDWLRQDQGHPLVVLRQILOWHUVIRUYLVXDOL]LQJ'$3,$OH[D)OXRUDQG 1HXURQDOVXEW\SHVDQGJOLDOFHOOSURSRUWLRQVLQWKHP\HQWHULFSOH[XVZHUHGHWHUPLQHGXVLQJWKH,PDJH - FHOO FRXQWHU PDQXDO IXQFWLRQ )RU HDFK VXEUHJLRQ WKH VXP RI &DOUHWLQLQ Q1RV DQG 6R[ FHOOV IURPWKHILHOGVRIYLHZZHUHQRUPDOL]HGWRWKHWRWDOQXPEHURI+X&'QHXURQV7KHWRWDOQXPEHURI +X&' QHXURQV ZHUH DOVR XVHG IRU TXDQWLILFDWLRQ RI QHXURQDO GHQVLW\ DQG H[SUHVVHG LQ QHXURQV SHU PP .

(48) Neurogastroenterology and Motility. dŽƵƌĠϴ . *,PRWLOLW\DVVD\V 7RWDO DQG SUR[LPDO LH VWRPDFK DQG VPDOO LQWHVWLQH FRPELQHG

(49)  *, WUDQVLWV ZHUH DVVHVVHG XVLQJ SUHYLRXVO\GHVFULEHGSURFHGXUHV%ULHIO\PLFHZHUHDGPLQLVWHUHGDVROXWLRQRIFDUPLQHUHGG\H 6LJPD$OGULFK &

(50)  GLVVROYHG LQ  PHWK\OFHOOXORVH 6LJPD$OGULFK 

(51)  YLD RUDO JDYDJH —OSHUJUDPRIZHLJKW

(52) )RUWKHWRWDO*,WUDQVLWPLFHZHUHWKHQUHWXUQHGWRLQGLYLGXDOFDJHVZLWKRXW IRRGDQGFDJHVZHUHLQVSHFWHGHYHU\PLQIRUWKHSUHVHQFHRIUHGSHOOHWV)RUHDFKPRXVHWKHWRWDO *,WUDQVLW ZDV H[SUHVVHGDVWKHWLPH LQKRXUPLQXWHV

(53) UHTXLUHG IURP JDYDJHWR H[SXOVLRQRIWKHILUVW. r ee rP Fo. UHG SHOOHW )RU WKH SUR[LPDO *, WUDQVLW PLFH ZHUH HXWKDQL]HG  PLQ DIWHU JDYDJH DQG WKHLU VPDOO LQWHVWLQH IURPGXRGHQXPWRLOHXP

(54) ZDVGLVVHFWHGRXW7KHGLVWDQFHWUDYHOOHGE\WKHFDUPLQHUHG G\H ZDV PHDVXUHG DQG H[SUHVVHG LQ SHUFHQWDJH RI WKH OHQJWK RI WKH HQWLUH VPDOO LQWHVWLQH 'LVWDO FRORQLF WUDQVLWZDVVWXGLHGYLDDEHDGH[SXOVLRQDVVD\HVVHQWLDOO\DVSUHYLRXVO\GHVFULEHG%ULHIO\RYHUQLJKW IDVWHG PLFH ZHUH DQHVWKHWL]HG ZLWK  LVRIOXUDQH DQG D PP JODVV EHDG ZDV LQWURGXFHG LQWR WKHLU FRORQZLWKDSUREHRYHUDGLVWDQFHRIFPIURPWKHDQXV RYHUODSSLQJERWKWKHSUR[LPDODQGPLG'&

(55) . ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 8 of 42. 7KHWLPHUHTXLUHGIRUH[SXOVLQJWKHJODVVEHDGZDVWDNHQDVDQHVWLPDWHRIGLVWDOFRORQLFWUDQVLW 6WDWLVWLFDODQDO\VLV. 'DWD DUH SUHVHQWHG DV WKH PHDQ “ VWDQGDUG GHYLDWLRQ ZHUH UHOHYDQW

(56)  ZLWK WKH QXPEHU Q

(57)  RI H[SHULPHQWVDQLPDOV LQFOXGHG LQ ILJXUHV DQGRU ILJXUH OHJHQGV 7KH VLJQLILFDQFH RI GLIIHUHQFHV ZDV HYDOXDWHGXVLQJWKHWDLOHG6WXGHQW VWWHVWH[FHSWIRU3HDUVRQ¶VFRUUHODWLRQDQDO\VHVIRUZKLFKWKH WDLOHG6WXGHQW VWWHVWZDVXVHG'LIIHUHQFHVZHUHFRQVLGHUHGVLJQLILFDQWIRUSYDOXHV”.

(58) Page 9 of 42. dŽƵƌĠϵ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r ee rP Fo. DFFXPXODWLRQRIIHFDOFRQWHQW7KHVHREVHUYDWLRQVUHYHDOHGDPDUNHGSURSHQVLW\WRIHFDOLPSDFWLRQLQ WKH FRORQ RI DGXOW 7DVK77J7J PDOHV ZKHQ FRPSDUHG WR DJH DQG JHQGHUPDWFKHG ZLOGW\SH FRQWUROV )LJXUH $% DQG 6XSSOHPHQWDO )LJXUH 

(59)  6LPLODUO\ WR WKH PDOHELDVHG DJDQJOLRQLF PHJDFRORQ SKHQRW\SHGLVSOD\HGE\WKLVOLQH7DVK77J7JIHPDOHVDSSHDUHGPXFKOHVVDIIHFWHG)XUWKHUPRUHZHDOVR REVHUYHG WKDW DGXOW 7DVK77J7J PLFH JDLQHG OHVV ZHLJKW WKDQ DJH DQG JHQGHUPDWFKHG FRQWUROV DQ RXWFRPHDJDLQDFFHQWXDWHGLQPDOHV 7DEOH

(60) . ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility. 7RIXUWKHUDQDO\]HWKHLQWHVWLQDOPRWLOLW\LQ7DVK77J7JPLFHWUDQVLWRIFDUPLQHUHGG\HDQGJODVVEHDG H[SXOVLRQ DVVD\V ZHUH XVHG LQ RUGHU WR UHFRUG WRWDO DQG SUR[LPDO LH VWRPDFK DQG VPDOO LQWHVWLQH FRPELQHG

(61)  *, WUDQVLWV DV ZHOO DV GLVWDO FRORQLF WUDQVLW UHVSHFWLYHO\ ,QWHUHVWLQJO\ D VWDWLVWLFDOO\ VLJQLILFDQWLQFUHDVHLQWKHDYHUDJHWRWDO*,WUDQVLWWLPHZDVVSHFLILFDOO\REVHUYHGIRU7DVK77J7JPDOHV )LJXUH$

(62) $QDO\VLVRISUR[LPDO*,WUDQVLWDQGGLVWDOFRORQLFWUDQVLWLQLVRODWLRQIXUWKHUDOORZHGXVWR ILQG WKDW VXFK UHGXFHG *, PRWLOLW\ LV QRW JOREDO ,QGHHG ZKLOH WKH SUR[LPDO *, WUDQVLW UHPDLQHG XQDIIHFWHG )LJXUH %

(63)  WKH DYHUDJH GLVWDO FRORQLF WUDQVLW WLPH ZDV IRXQG WR EH IROG JUHDWHU LQ 7DVK77J7J PDOHV )LJXUH &

(64)  ,Q PDUNHG FRQWUDVW 7DVK77J7J IHPDOHV ZHUH FRPSDUDEOH WR ZLOGW\SH FRQWUROV LQ DOO *, PRWLOLW\ DVVD\V )LJXUH $&

(65)  7DNHQ WRJHWKHU WKHVH REVHUYDWLRQV VWURQJO\ VXJJHVW WKDWDGXOW7DVK77J7JPDOHVEXWQRWIHPDOHVVXIIHUIURPFKURQLFFRQVWLSDWLRQ .

(66) Neurogastroenterology and Motility. dŽƵƌĠϭϬ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r ee rP Fo. WKHP\HQWHULFSOH[XVZDVQRWHGLQWKHPLGFRORQ 0&

(67) DQGWKHGLVWDOFRORQ '&

(68) DQGWKLVZDVIRXQGWR EHFRPELQHGZLWKGLVWDODJDQJOLRQRVLVLQDSSUR[LPDWHO\KDOIRIWKHVWXGLHGFDVHV )LJXUH$&

(69) 6XFK GHFUHDVHG GHQVLW\ LV QRW GXH WR FRORQ GLVWHQWLRQ 6XSSOHPHQWDO )LJXUH 

(70)  DQG ZDV DOVR REVHUYHG LQ DQRWKHUVDPSOHVHULHVXVLQJDQWL+X&'LPPXQRIOXRUHVFHQFH )LJXUH'DQG6XSSOHPHQWDO)LJXUH

(71)  $VGRFXPHQWHGLQRXUSULRUVWXG\WKHDJDQJOLRQLFVHJPHQWRQO\FRQWDLQVODUJHH[WULQVLFQHUYHILEHUV W\SLFDOO\ DVVRFLDWHG ZLWK VXFK UHJLRQ 1R REYLRXV DQGRU FRQVLVWHQW FKDQJHV LQ P\HQWHULF SOH[XV. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 10 of 42. GHQVLW\ZDVQRWHGLQWKHSUR[LPDOFRORQ 3&

(72) DQGWKHGXRGHQXP )LJXUH$DQG6XSSOHPHQWDO)LJXUH 

(73)  7KHVH REVHUYDWLRQV WKXV LQGLFDWH WKDW LQ FRPSDULVRQ WR WKH LPPDWXUH 7DVK77J7J SRSXODWLRQ WKDW LQFOXGHV PHJDFRORQVXIIHULQJ DQLPDOV  WKH DGXOW SRSXODWLRQ DSSHDUV HQULFKHG LQ DQLPDOV KDYLQJ D IXOO\ JDQJOLRQDWHG FRORQ DOWKRXJK (16 GHQVLW\ LV VLJQLILFDQWO\ UHGXFHG LQ WKHLU 0& DQG '& :H EHOLHYHWKDWWKHUHDVRQZK\QRLPPDWXUH7DVK77J7JPDOHZLWKDIXOO\JDQJOLRQDWHGFRORQZDVLGHQWLILHG LQ RXU SUHYLRXV VWXG\ LV PRVW OLNHO\ GXH WR WKH VPDOO QXPEHU RI QRQPHJDFRORQVXIIHULQJ DQLPDOV LQ WKLVJURXS PDOHVRQO\

(74)  )URPQRZRQWKHVXEJURXSRI7DVK77J7J PLFHZLWKRXWDJDQJOLRQRVLVZLOO EH UHIHU WR DV ³K\SRJDQJOLRQLF´ ZKHUHDV WKH VXEJURXS RI 7DVK77J7J PLFH H[KLELWLQJ ERWK K\SRJDQJOLRQRVLVDQGGLVWDODJDQJOLRQRVLVZLOOEHUHIHUWRDV³DJDQJOLRQLF´ 6H[VWUDWLILHGDQDO\VLVRIWKHDERYHSKHQRW\SHVUHYHDOHGWKDWLQFRPSDULVRQWRIHPDOHVPDOHVDUHPRUH RIWHQVXEMHFWHGWRVKRUWVHJPHQWGLVWDODJDQJOLRQRVLV$FFRUGLQJO\WKHDYHUDJHH[WHQWRIDJDQJOLRQRVLV.

(75) Page 11 of 42. dŽƵƌĠϭϭ . ZDVIRXQGWREHVLJQLILFDQWO\KLJKHULQPDOHVFRPSDUHGWRIHPDOHV )LJXUH%

(76) 0RUHRYHUDOWKRXJKWKH P\HQWHULFSOH[XVGHQVLW\IRUWKHDGXOW7DVK77J7JSRSXODWLRQDVDZKROHDSSHDUVVLJQLILFDQWO\UHGXFHGLQ FRPSDULVRQ WR DJHPDWFKHG FRQWUROV WKLV GHFUHDVH LV PRUH DFFHQWXDWHG LQ PDOHV E\ D IDFWRU RI DSSUR[LPDWHO\ IROG ZLWK $&K( KLVWRFKHPLVWU\ GDWD  YHUVXV  GHFUHDVH LQ WKH 0& DQG YHUVXVGHFUHDVHLQWKH'&ZLWK+X&'LPPXQRIOXRUHVFHQFHGDWDYHUVXV GHFUHDVH LQ WKH 0& DQG  YHUVXV  GHFUHDVH LQ WKH '&

(77)  )LJXUH &' DQG 6XSSOHPHQWDO )LJXUH %

(78)  'LUHFW FRPSDULVRQ RI P\HQWHULF SOH[XV GHQVLW\ EHWZHHQ 7DVK77J7J PDOHV DQG IHPDOHV. r ee rP Fo. IXUWKHU UHYHDOHG VWDWLVWLFDOO\ VLJQLILFDQW GLIIHUHQFHV XVLQJ $&K( KLVWRFKHPLVWU\ GDWD EXW QRW XVLQJ +X&' LPPXQRIOXRUHVFHQFH GDWD 6XSSOHPHQWDO )LJXUH 

(79)  7KHUHIRUH DJDLQ LQ OLQH ZLWK WKH PDOH ELDVHGDJDQJOLRQLFPHJDFRORQSKHQRW\SHSUHYLRXVO\GHVFULEHGIRULPPDWXUH7DVK77J7JPLFHWKHUHLV D VWURQJ PDOH ELDV LQ WKH H[SUHVVLYLW\VHYHULW\ RI ERWK K\SRJDQJOLRQRVLV DQG VKRUW VHJPHQW DJDQJOLRQRVLVLQWKHFRORQRIDGXOW7DVK77J7JPLFH. &RUUHODWLRQEHWZHHQLPSDLUHGFRORQLFPRWLOLW\DQGDJDQJOLRQRVLVK\SRJDQJOLRQRVLVLQDGXOW 7DVK77J7JPLFH. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility. &RPELQLQJRXUDQDO\VHVRIP\HQWHULFSOH[XVDUFKLWHFWXUHDQG*,PRWLOLW\SRLQWHGWRZDUGVWKHH[LVWHQFH RIDGLUHFWOLQNEHWZHHQWKHLGHQWLILHGPDOHELDVHGP\HQWHULFSOH[XVGHIHFWV K\SRJDQJOLRQRVLVDQGRU VKRUWVHJPHQWDJDQJOLRQRVLV

(80) DQGWKHPDOHVSHFLILFFRORQLFG\VPRWLOLW\,QWHUHVWLQJO\JLYHQWKDWDOPRVW HYHU\WHVWHG7DVK7DQLPDOZDVHYDOXDWHGIRUDOOWKHVHSDUDPHWHUVDQGWKDWG\VPRWLOLW\ZDVSUHVHQWLQ ERWKWKH³K\SRJDQJOLRQLF´DQG³DJDQJOLRQLF´VXEJURXSVRI7DVK7DQLPDOV )LJXUH&

(81) WKLVDOORZHGXV WR DVVHVV WKH UHODWLYH FRQWULEXWLRQ RI GLIIHUHQW VWUXFWXUDO GHIHFWV LH K\SRJDQJOLRQRVLV ZLWKRXW DJDQJOLRQRVLV YHUVXV H[WHQW RI DJDQJOLRQRVLV

(82)  WR WKH GHFUHDVHG FRORQ PRWLOLW\ ,Q ERWK FDVHV PRGHVW FRUUHODWLRQV ZHUH GHWHFWHG )LJXUH 

(83)  7KH FRPSDULVRQ RI FRUUHODWLRQ FRHIILFLHQWV UHYHDOHG D VOLJKWO\ VWURQJHUUHODWLRQVKLSEHWZHHQGLVWDOFRORQLFWUDQVLWWLPHDQGP\HQWHULFSOH[XVGHQVLW\ U 

(84) WKDQ EHWZHHQ GLVWDO FRORQLF WUDQVLW WLPH DQG H[WHQW RI DJDQJOLRQRVLV U  

(85)  $OWKRXJK VWDWLVWLFDO.

(86) Neurogastroenterology and Motility. dŽƵƌĠϭϮ . VLJQLILFDQFH ZDV QRW UHDFKHG PRVW OLNHO\ EHFDXVH RI WKH VPDOO VDPSOH VL]H WKHVH UHVXOWV VXJJHVW WKDW ERWK K\SRJDQJOLRQRVLV DQG DJDQJOLRQRVLV WDNHQ VHSDUDWHO\ PLJKW SDUWLDOO\ FRQWULEXWH WR WKH LPSDLUHG FRORQLFPRWLOLW\REVHUYHGLQ7DVK77J7JPDOHV+RZHYHUWKHODFNRIFRUUHODWLRQEHWZHHQGLVWDOFRORQLF WUDQVLWWLPHDQGP\HQWHULFSOH[XVGHQVLW\LQ7DVK77J7J IHPDOHV )LJXUH$

(87) FRPELQHGWRWKHIDFWWKDW DOO7DVK77J7J IHPDOHV ERWK³K\SRJDQJOLRQLF´DQG³DJDQJOLRQLF´

(88) H[KLELWQRUPDOPRWLOLW\ )LJXUH&

(89)  VWURQJO\ VXJJHVWV WKDW WKHVH (16 VWUXFWXUDO GHIHFWV DUH QRW VXIILFLHQW IRU H[SODLQLQJ WKH PDOHVSHFLILF FRORQG\VPRWLOLW\RI7DVK77J7JPLFH. r ee rP Fo. 0DOHVSHFLILFUHJLRQDODOWHUDWLRQRIWKHQHXURFKHPLFDOFRGLQJRIP\HQWHULFJDQJOLDLQWKHGLVWDO FRORQRIDGXOW7DVK77J7JPLFH. $V QHXURQDO VXEW\SHV DQGRU JOLDQHXURQ UDWLR LPEDODQFH PLJKW DOVR FRQWULEXWH WR WKH REVHUYHG PDOH VSHFLILFFRORQLFG\VPRWLOLW\ZHVXEVHTXHQWO\H[DPLQHGWKHUHODWLYHDEXQGDQFHRIJOLDOFHOOV 6R[

(90)  DV ZHOO DV WKH SURSRUWLRQ RI WKH PDLQ SRSXODWLRQV RI LQKLELWRU\ Q1RV

(91)  DQG DFWLYDWLQJ &DOUHWLQLQ

(92)  QHXURQVLQP\HQWHULFJDQJOLDIURPWKHPLG'&XVLQJWKHGXRGHQXPDVDFRQWUROUHJLRQ )LJXUHV

(93) . ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 12 of 42. ,Q DFFRUGDQFH ZLWK WKH QRUPDO PRWLOLW\ GHWHFWHG LQ WKH DQWHULRU *, WUDFW )LJXUH %

(94)  WKH DYHUDJH SURSRUWLRQRI&DOUHWLQLQDQGQ1RVQHXURQVZDVVLPLODULQWKHGXRGHQXPRIZLOGW\SHDQG7DVK77J7J PLFHIRUERWK JHQGHUV )LJXUHV$¶%¶DQG$¶%¶

(95) 6LPLODUO\QRFKDQJH ZDVIRXQGLQWKH DYHUDJH SURSRUWLRQRI&DOUHWLQLQQHXURQVDVZHOODVLQWKHJOLDQHXURQUDWLRLQP\HQWHULFJDQJOLDIURPWKHPLG '& RI 7DVK77J7J DQLPDOV )LJXUH  DQG 6XSSOHPHQWDO )LJXUH 

(96)  +RZHYHU ZKLOH WKH DYHUDJH SURSRUWLRQRIQ1RVQHXURQVZDVFRPSDUDEOHEHWZHHQZLOGW\SHDQG7DVK77J7JIHPDOHVHLWKHULQWKLV VDPHUHJLRQ )LJXUH%%¶

(97) RULQWKHGLVWDOPRVWJDQJOLRQDWHGUHJLRQ 6XSSOHPHQWDO)LJXUH

(98) D LQFUHDVH LQ WKH DYHUDJH SURSRUWLRQ RI Q1RV QHXURQV ZDV VSHFLILFDOO\ REVHUYHG LQ WKH GLVWDO 0& RI 7DVK77J7J PDOHV )LJXUH $$¶

(99)  2I QRWH WKLV IROG LQFUHDVH RI QLWUHUJLF QHXURQV ZDV IRXQG WR EH UHJLRQDOO\ UHVWULFWHG DV QR FKDQJH ZDV REVHUYHG LQ WKH SUR[LPDO 0& 6XSSOHPHQWDO )LJXUH 

(100)  $OWKRXJK ZH GR QRW H[FOXGH WKH SRVVLELOLW\ WKDW RWKHU OHVV DEXQGDQW QHXURQ VXEW\SHV PLJKW DOVR EH.

(101) Page 13 of 42. dŽƵƌĠϭϯ . DIIHFWHG ZH EHOLHYH WKDW VXFK D UHJLRQDOO\ UHVWULFWHG LQFUHDVH LQ WKH PDLQ SRSXODWLRQ RI UHOD[LQJ QHXURQVFRXOGFRQWULEXWHWRWKHPDOHVSHFLILFGLVWDOFRORQLFG\VPRWLOLW\  6WDWXVRILQWHUVWLWLDOFHOOVRI&DMDOQHWZRUNVLQWKHFRORQRIDGXOW7DVK77J7JPLFH )RUERWKKXPDQSDWLHQWVDQGPRXVHPRGHOVDOWHUHGQXPEHUVRILQWHUVWLWLDOFHOOVRI&DMDO ,&&

(102) ±WKH*, SDFHPDNHUFHOOV±DUHRIWHQREVHUYHGLQDVVRFLDWLRQZLWK(16GHIHFWV7RGHWHUPLQHZKHWKHUWKHVH F.LW QRQQHXUDO FUHVWGHULYHG FHOOV PLJKW DGGLWLRQDOO\ FRQWULEXWH WR WKH PDOHELDVHG FRORQLF. r ee rP Fo. G\VPRWLOLW\RIDGXOW7DVK77J7JPLFHWKHLUSUHVHQFHDQGJURVVGLVWULEXWLRQZHUHH[DPLQHGDWGLIIHUHQW GHSWKOHYHOVZLWKLQWKHZDOORIWKHK\SRJDQJOLRQLF'&7KLVDQDO\VLVUHYHDOHGQRRYHUWFKDQJHLQWKH UHODWLYH SUHVHQFH DQG GLVWULEXWLRQ RI ,&& VXESRSXODWLRQV ZLWKLQ WKH ORQJLWXGLQDO DQG FLUFXODU VPRRWK PXVFOHOD\HUVDVZHOODVDWWKHOHYHORIERWKWKHP\HQWHULFDQGGHHSPXVFXODULVSOH[XVHV 6XSSOHPHQWDO )LJXUH 

(103)  7KHUHIRUH WKHVH UHVXOWV VWURQJO\ VXJJHVW WKDW WKH PDOHELDVHG FRORQLF G\VPRWLOLW\ RI 7DVK77J7JPLFHLVVWULFWO\GXHWRQHXURQDOGHIHFWV . . ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility.

(104) Neurogastroenterology and Motility. dŽƵƌĠϭϰ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r ee rP Fo. PDOHELDVHGG\VPRWLOLW\FRXOGEHPXOWLIDFWRULDODQGLQFOXGHDUROHIRUPDOHVSHFLILFQHXURQDOVXEW\SHV LPEDODQFH :H EHOLHYH WKDW WKHVH ILQGLQJV FRXOG KDYH FOLQLFDO UHOHYDQFH IRU WKH PDQDJHPHQW RI SRVWRSHUDWLYH+6&5SDWLHQWVDVZHOODVRISDWLHQWVGLDJQRVHGIRURWKHUHQWHULFQHXURSDWKLHV . 5ROHRIP\HQWHULFSOH[XVGHQVLW\LQWKHPDOHELDVHGFRORQLFPRWLOLW\GHIHFWRI7DVK77J7JPLFH 2QHRIWKHPRVWLQWHUHVWLQJIHDWXUHVRIWKHDJDQJOLRQRVLVSKHQRW\SHRI7DVK77J7JPLFHLVLWVLQFRPSOHWH. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 14 of 42. SHQHWUDQFH )LJXUH $%

(105)  ,Q WKLV ZRUN ZH WRRN DGYDQWDJH RI WKLV FKDUDFWHULVWLF IRU VSHFLILFDOO\ DVVHVVLQJ WKH UHODWLYH FRQWULEXWLRQ RI DJDQJOLRQRVLV DQG K\SRJDQJOLRQRVLV WR WKH PDOHELDVHG FRORQLF PRWLOLW\GHIHFW ,QWULJXLQJO\ZH ILUVWREVHUYHGWKDWQRWRQO\³DJDQJOLRQLF´EXW DOVRDKLJKQXPEHURI ZKDW ZH QDPHG ³K\SRJDQJOLRQLF´ 7DVK77J7J DQLPDOV ZHUH SUHVHQW LQ WKH JURXS RI PDOHV H[KLELWLQJ FRORQLFWUDQVLWWLPHKLJKHUWKDQZLOGW\SHFRQWUROV )LJXUH&

(106) 0RUHLQWULJXLQJZDVWKHIDFWWKDWVRPH RIWKHVH³K\SRJDQJOLRQLF´7DVK77J7JPDOHVZHUHHYHQPRUHVHYHUHO\DIIHFWHGWKDQVRPH³DJDQJOLRQLF´ DQLPDOV $FFRUGLQJO\ RXU FRUUHODWLRQ DQDO\VHV VXJJHVWHG WKDW GLVWDO FRORQLF WUDQVLW WLPH ZDV PRUH UREXVWO\OLQNHGWRP\HQWHULFSOH[XVGHQVLW\UDWKHUWKDQWRH[WHQWRIVKRUWVHJPHQWDJDQJOLRQRVLV )LJXUH 

(107) $OWKRXJKWKHQHJDWLYHUHODWLRQVKLSEHWZHHQP\HQWHULFSOH[XVGHQVLW\DQGPRWLOLW\GHVFULEHGLQRXU VWXG\ GLG QRW UHDFK VWDWLVWLFDO VLJQLILFDQFH WKLV UHVXOW LV LQ DJUHHPHQW ZLWK SULRU VWXGLHV UHSRUWLQJ DOWHUHGPRWLOLW\LQWKHK\SRJDQJOLRQLFERZHOVHJPHQWVRI(GQUE(GQ*GQI+DQGDQG5DOGKPXWDQW.

(108) Page 15 of 42. dŽƵƌĠϭϱ . PLFH+RZHYHULWLVQRWHZRUWK\WKDWQRVXFKFRUUHODWLRQZDVREVHUYHGIRU7DVK77J7JIHPDOHV 2QH VLPSOH H[SODQDWLRQIRU WKLV VH[ ELDV PLJKW EH WKDW WKH GHFUHDVH LQ P\HQWHULF QHXURQDO GHQVLW\ RI 7DVK77J7JIHPDOHVUDQJLQJEHWZHHQDQG )LJXUH&'DQG6XSSOHPHQWDO)LJXUHV%DQG %¶

(109) LVQRWVXIILFLHQWIRULQWHUIHULQJZLWKFRORQLFPRWLOLW\DWOHDVWLQWKH)9%1PRXVHVWUDLQ,QGHHG LQ7DVK77J7JPDOHVWKLVGHFUHDVHZDVFDOFXODWHGWREH• )LJXUH&'DQG6XSSOHPHQWDO)LJXUH %

(110) 7DNHQWRJHWKHUZLWKWKHGDWDREWDLQHGZLWKWKHRWKHUPRGHOVPHQWLRQHGDERYHLQZKLFKQHXURQDO ORVV ZDV •    WKLV VWURQJO\ VXJJHVWV WKDW D a GHFUHDVH RI P\HQWHULF QHXURQDO GHQVLW\. r ee rP Fo. PLJKW UHSUHVHQW D WKUHVKROG OHYHO DERYH ZKLFK LPSDLUPHQW RI GLVWDO FRORQ PRWLOLW\ LV PRUH OLNHO\ WR RFFXU . 5ROH RI P\HQWHULF QHXURQDO VXEW\SHV LPEDODQFH LQ WKH PDOHELDVHG FRORQLF PRWLOLW\ GHIHFW RI 7DVK77J7JPLFH. $Q DOWHUQDWLYH DQG QRW QHFHVVDU\ PXWXDOO\ H[FOXVLYH SRVVLELOLW\ IRU H[SODLQLQJ WKH QRUPDO FRORQLF. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility. PRWLOLW\ RI7DVK77J7J IHPDOHV FRXOG EH WKDW K\SRJDQJOLRQRVLV DORQH LV QRW VXIILFLHQW IRU VLJQLILFDQWO\ LPSDFWLQJ FRORQLF WUDQVLW ,Q VWURQJ VXSSRUW RI WKLV SRVVLELOLW\ RXU DQDO\VLV RI Q1RV DQG &DOUHWLQLQ QHXURQDO VXEW\SHV ± WKH PDLQ PDUNHUV RI LQKLELWRU\ DQG DFWLYDWLQJ P\HQWHULF QHXURQV ± UHYHDOHG D PDOHVSHFLILF IROG LQFUHDVH RI QLWUHUJLF QHXURQV UHVWULFWHG WR WKH PRVW GLVWDO JDQJOLRQDWHG UHJLRQ )LJXUH 

(111)  $OWKRXJK WKH SURSRUWLRQ RI PRUH GLVFUHWH VXEW\SHV PLJKW DOVR EH DIIHFWHG ZH WKLQN WKDW GRXEOLQJ WKH DPRXQW RI Q1RV QHXURQV IURP  WR  RI DOO P\HQWHULF QHXURQV RI WKH FRORQ

(112)  LV PRVWOLNHO\VXIILFLHQWE\LWVHOIWRVLJQLILFDQWO\LQIOXHQFHPRWLOLW\9HU\LQWHUHVWLQJO\VXFKDUHJLRQDOO\ UHVWULFWHG LQFUHDVH RI QLWUHUJLF QHXURQV KDV DOVR EHHQ SUHYLRXVO\ UHSRUWHG LQ RWKHU +6&5 PRXVH PRGHOV   ,Q WKLV UHJDUG WKH VLPLODULWLHV ZLWK PRXVH PRGHOV KDYLQJ LPSDLUHG (GQ(GQUE VLJQDOLQJDUHHVSHFLDOO\VWULNLQJ,QGHHGLQERWK(GQUEDQG(GQPLFHDQLGHQWLFDOaIROGLQFUHDVH RIQ1RVQHXURQVLVVSHFLILFDOO\REVHUYHGLQWKHPRVWGLVWDOJDQJOLRQDWHGUHJLRQV,Q(GQUEPLFH.

(113) Neurogastroenterology and Motility. dŽƵƌĠϭϲ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r ee rP Fo. WKH PRVW GLVWDO JDQJOLRQDWHG FRORQ UHJLRQ RI 7DVK77J7J PDOHV IXUWKHU VXJJHVWV WKDW LW RQO\ RFFXUV LQ UHVSRQVHWRK\SRJDQJOLRQRVLVDQGRUDJDQJOLRQRVLV,QDJUHHPHQWZLWKWKLVK\SRWKHVLVQ1RVWUDQVFULSW OHYHOVDUHHYHQIRXQGWREHGHFUHDVHGLQ7DVK77J7JHHQWHULFQHXUDOSURJHQLWRUV . ,PSOLFDWLRQVIRU+6&5DQGRWKHUHQWHULFQHXURSDWKLHV. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 16 of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

(114) Page 17 of 42. dŽƵƌĠϭϳ .  $&.12:/('*(0(176 7KH DXWKRUV WKDQN 'HQLV )OLSR 84$0

(115)  IRU DVVLVWDQFH ZLWK FRQIRFDO LPDJLQJ DQG DOO WKH RWKHU PHPEHUVRIWKH3LORQODEIRUWKRXJKWIXOGLVFXVVLRQVDERXWWKHPDQXVFULSW  )81',1* 7KLV ZRUN ZDV VXSSRUWHG E\ JUDQWV IURP WKH 1DWXUDO 6FLHQFHV DQG (QJLQHHULQJ 5HVHDUFK &RXQFLO RI. r ee rP Fo. &DQDGD 16(5&

(116) DQGIURPWKH&DQDGLDQ,QVWLWXWHVRI+HDOWK5HVHDUFK &,+5023

(117)  WR13$07ZDVVXSSRUWHGE\D3K'VFKRODUVKLSIURPWKH)RQGVGHODUHFKHUFKHGX4XpEHF1DWXUHHW WHFKQRORJLHV )5417

(118)  13LVD)RQGVGHOD5HFKHUFKHGX4XpEHF6DQWp )546

(119) -XQLRU5HVHDUFK 6FKRODUDQGWKHUHFLSLHQWRIWKH84$05HVHDUFK&KDLURQ5DUH*HQHWLF'LVHDVHV7KHIXQGHUVKDGQR UROHLQVWXG\GHVLJQGDWDFROOHFWLRQDQGDQDO\VLVGHFLVLRQWRSXEOLVKRUSUHSDUDWLRQRIWKHPDQXVFULSW  ',6&/2685( 1RFRPSHWLQJLQWHUHVWVGHFODUHG  $87+25&2175,%87,21. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility. $07GHVLJQHGWKHH[SHULPHQWV$07DQG%&SHUIRUPHGWKHH[SHULPHQWV$07LQWHUSUHWHGGDWD13 VXSHUYLVHGWKHVWXG\$07DQG13ZURWHWKHPDQXVFULSW$OODXWKRUVUHYLHZHGDQGDSSURYHGWKHILQDO PDQXVFULSW  . .

(120) Neurogastroenterology and Motility. dŽƵƌĠϭϴ . 5()(5(1&(6  ϭ͘ 'ŽůĚƐƚĞŝŶD͕,ŽĨƐƚƌĂZDĂŶĚƵƌŶƐ:͘ƵŝůĚŝŶŐĂďƌĂŝŶŝŶƚŚĞŐƵƚ͗ĚĞǀĞůŽƉŵĞŶƚŽĨƚŚĞĞŶƚĞƌŝĐ ŶĞƌǀŽƵƐƐLJƐƚĞŵ͘ůŝŶ'ĞŶĞƚ͘ϮϬϭϯ͖ϴϯ͗ϯϬϳͲϭϲ͘ Ϯ͘ >ĂŬĞ:/ĂŶĚ,ĞƵĐŬĞƌŽƚŚZK͘ŶƚĞƌŝĐŶĞƌǀŽƵƐƐLJƐƚĞŵĚĞǀĞůŽƉŵĞŶƚ͗ŵŝŐƌĂƚŝŽŶ͕ĚŝĨĨĞƌĞŶƚŝĂƚŝŽŶ͕ĂŶĚ ĚŝƐĞĂƐĞ͘ŵĞƌŝĐĂŶũŽƵƌŶĂůŽĨƉŚLJƐŝŽůŽŐLJ'ĂƐƚƌŽŝŶƚĞƐƚŝŶĂůĂŶĚůŝǀĞƌƉŚLJƐŝŽůŽŐLJ͘ϮϬϭϯ͖ϯϬϱ͗'ϭͲϮϰ͘ ϯ͘ &ƵƌŶĞƐƐ:͘dŚĞĞŶƚĞƌŝĐŶĞƌǀŽƵƐƐLJƐƚĞŵĂŶĚŶĞƵƌŽŐĂƐƚƌŽĞŶƚĞƌŽůŽŐLJ͘EĂƚZĞǀ'ĂƐƚƌŽĞŶƚĞƌŽů,ĞƉĂƚŽů͘ ϮϬϭϮ͖ϵ͗ϮϴϲͲϵϰ͘ ϰ͘ DƵƐƐĞƌDĂŶĚDŝĐŚĞůůĞ^ŽƵƚŚĂƌĚͲ^ŵŝƚŚ͘ĂůĂŶĐŝŶŐŽŶƚŚĞĐƌĞƐƚͲǀŝĚĞŶĐĞĨŽƌĚŝƐƌƵƉƚŝŽŶŽĨƚŚĞ ĞŶƚĞƌŝĐŐĂŶŐůŝĂǀŝĂŝŶĂƉƉƌŽƉƌŝĂƚĞůŝŶĞĂŐĞƐĞŐƌĞŐĂƚŝŽŶĂŶĚĐŽŶƐĞƋƵĞŶĐĞƐĨŽƌŐĂƐƚƌŽŝŶƚĞƐƚŝŶĂůĨƵŶĐƚŝŽŶ͘ĞǀŝŽů͘ ϮϬϭϯ͖ϯϴϮ͗ϯϱϲͲϲϰ͘ ϱ͘ ŵŝĞů:͕^ƉƌŽĂƚͲŵŝƐŽŶ͕'ĂƌĐŝĂͲĂƌĐĞůŽD͕ĞƚĂů͘,ŝƌƐĐŚƐƉƌƵŶŐĚŝƐĞĂƐĞ͕ĂƐƐŽĐŝĂƚĞĚƐLJŶĚƌŽŵĞƐĂŶĚ ŐĞŶĞƚŝĐƐ͗ĂƌĞǀŝĞǁ͘:DĞĚ'ĞŶĞƚ͘ϮϬϬϴ͖ϰϱ͗ϭͲϭϰ͘ ϲ͘ ĞƌŐĞƌŽŶ<&͕^ŝůǀĞƌƐŝĚĞƐtĂŶĚWŝůŽŶE͘dŚĞĚĞǀĞůŽƉŵĞŶƚĂůŐĞŶĞƚŝĐƐŽĨ,ŝƌƐĐŚƐƉƌƵŶŐΖƐĚŝƐĞĂƐĞ͘ůŝŶ 'ĞŶĞƚ͘ϮϬϭϯ͖ϴϯ͗ϭϱͲϮϮ͘ ϳ͘ KďĞƌŵĂLJƌ&͕,ŽƚƚĂZ͕ŶŽŵŽƚŽ,ĂŶĚzŽƵŶŐ,D͘ĞǀĞůŽƉŵĞŶƚĂŶĚĚĞǀĞůŽƉŵĞŶƚĂůĚŝƐŽƌĚĞƌƐŽĨƚŚĞ ĞŶƚĞƌŝĐŶĞƌǀŽƵƐƐLJƐƚĞŵ͘EĂƚZĞǀ'ĂƐƚƌŽĞŶƚĞƌŽů,ĞƉĂƚŽů͘ϮϬϭϯ͖ϭϬ͗ϰϯͲϱϳ͘ ϴ͘ ZŝŶƚĂůĂZ:ĂŶĚWĂŬĂƌŝŶĞŶDW͘>ŽŶŐͲƚĞƌŵŽƵƚĐŽŵĞƐŽĨ,ŝƌƐĐŚƐƉƌƵŶŐΖƐĚŝƐĞĂƐĞ͘^ĞŵŝŶWĞĚŝĂƚƌ^ƵƌŐ͘ϮϬϭϮ͖ Ϯϭ͗ϯϯϲͲϰϯ͘ ϵ͘ &ƌŝĞĚŵĂĐŚĞƌ&ĂŶĚWƵƌŝW͘ůĂƐƐŝĨŝĐĂƚŝŽŶĂŶĚĚŝĂŐŶŽƐƚŝĐĐƌŝƚĞƌŝĂŽĨǀĂƌŝĂŶƚƐŽĨ,ŝƌƐĐŚƐƉƌƵŶŐΖƐĚŝƐĞĂƐĞ͘ WĞĚŝĂƚƌŝĐƐƵƌŐĞƌLJŝŶƚĞƌŶĂƚŝŽŶĂů͘ϮϬϭϯ͖Ϯϵ͗ϴϱϱͲϳϮ͘ ϭϬ͘ ĞƚƚŽůůŝD͕ĞĂƌůŝ͕:ŽůŝŶͲĂŚĞů<͕ĞƚĂů͘ŽůŽŶŝĐĚLJƐŵŽƚŝůŝƚLJŝŶƉŽƐƚƐƵƌŐŝĐĂůƉĂƚŝĞŶƚƐǁŝƚŚ ,ŝƌƐĐŚƐƉƌƵŶŐΖƐĚŝƐĞĂƐĞ͘WŽƚĞŶƚŝĂůƐŝŐŶŝĨŝĐĂŶĐĞŽĨĂďŶŽƌŵĂůŝƚŝĞƐŝŶƚŚĞŝŶƚĞƌƐƚŝƚŝĂůĐĞůůƐŽĨĂũĂůĂŶĚƚŚĞĞŶƚĞƌŝĐ ŶĞƌǀŽƵƐƐLJƐƚĞŵ͘:WĞĚŝĂƚƌ^ƵƌŐ͘ϮϬϬϴ͖ϰϯ͗ϭϰϯϯͲϴ͘ ϭϭ͘ ƵƌŶƐ:͕ZŽďĞƌƚƐZZ͕ŽƌŶƐƚĞŝŶ:ĂŶĚzŽƵŶŐ,D͘ĞǀĞůŽƉŵĞŶƚŽĨƚŚĞĞŶƚĞƌŝĐŶĞƌǀŽƵƐƐLJƐƚĞŵĂŶĚŝƚƐ ƌŽůĞŝŶŝŶƚĞƐƚŝŶĂůŵŽƚŝůŝƚLJĚƵƌŝŶŐĨĞƚĂůĂŶĚĞĂƌůLJƉŽƐƚŶĂƚĂůƐƚĂŐĞƐ͘^ĞŵŝŶWĞĚŝĂƚƌ^ƵƌŐ͘ϮϬϬϵ͖ϭϴ͗ϭϵϲͲϮϬϱ͘ ϭϮ͘ ^ƚƌƵŝũƐD͕ŝĂŵŽŶĚ/Z͕WĞŶĐŚĂƌnjW͕ĞƚĂů͘ďƐĞŶĐĞŽĨƚŚĞŝŶƚĞƌƐƚŝƚŝĂůĐĞůůƐŽĨĂũĂůŝŶĂĐŚŝůĚǁŝƚŚ ĐŚƌŽŶŝĐƉƐĞƵĚŽŽďƐƚƌƵĐƚŝŽŶ͘:WĞĚŝĂƚƌ^ƵƌŐ͘ϮϬϬϴ͖ϰϯ͗ĞϮϱͲϵ͘ ϭϯ͘ 'ŝĂŶŝŶŽ^͕'ƌŝĚĞƌ:Z͕ƌĞƐƐǁĞůů:͕ŶŽŵŽƚŽ,ĂŶĚ,ĞƵĐŬĞƌŽƚŚZK͘'E&ĂǀĂŝůĂďŝůŝƚLJĚĞƚĞƌŵŝŶĞƐĞŶƚĞƌŝĐ ŶĞƵƌŽŶŶƵŵďĞƌďLJĐŽŶƚƌŽůůŝŶŐƉƌĞĐƵƌƐŽƌƉƌŽůŝĨĞƌĂƚŝŽŶ͘ĞǀĞůŽƉŵĞŶƚ͘ϮϬϬϯ͖ϭϯϬ͗ϮϭϴϳͲϵϴ͘ ϭϰ͘ ZŽ^͕,ǁĂŶŐ^:͕DƵƚŽD͕:ĞǁĞƚƚt<ĂŶĚ^ƉĞŶĐĞƌE:͘ŶĂƚŽŵŝĐŵŽĚŝĨŝĐĂƚŝŽŶƐŝŶƚŚĞĞŶƚĞƌŝĐŶĞƌǀŽƵƐ ƐLJƐƚĞŵŽĨƉŝĞďĂůĚŵŝĐĞĂŶĚƉŚLJƐŝŽůŽŐŝĐĂůĐŽŶƐĞƋƵĞŶĐĞƐƚŽĐŽůŽŶŝĐŵŽƚŽƌĂĐƚŝǀŝƚLJ͘ŵĞƌŝĐĂŶũŽƵƌŶĂůŽĨ ƉŚLJƐŝŽůŽŐLJ'ĂƐƚƌŽŝŶƚĞƐƚŝŶĂůĂŶĚůŝǀĞƌƉŚLJƐŝŽůŽŐLJ͘ϮϬϬϲ͖ϮϵϬ͗'ϳϭϬͲϴ͘ ϭϱ͘ ZŽďĞƌƚƐZZ͕ŽƌŶƐƚĞŝŶ:͕ĞƌŐŶĞƌ:ĂŶĚzŽƵŶŐ,D͘ŝƐƚƵƌďĂŶĐĞƐŽĨĐŽůŽŶŝĐŵŽƚŝůŝƚLJŝŶŵŽƵƐĞŵŽĚĞůƐ ŽĨ,ŝƌƐĐŚƐƉƌƵŶŐΖƐĚŝƐĞĂƐĞ͘ŵĞƌŝĐĂŶũŽƵƌŶĂůŽĨƉŚLJƐŝŽůŽŐLJ'ĂƐƚƌŽŝŶƚĞƐƚŝŶĂůĂŶĚůŝǀĞƌƉŚLJƐŝŽůŽŐLJ͘ϮϬϬϴ͖Ϯϵϰ͗ 'ϵϵϲͲ'ϭϬϬϴ͘ ϭϲ͘ ^ŚĞŶ>͕WŝĐŚĞů:'͕DĂLJĞůŝd͕^ĂƌŝŽůĂ,͕>ƵĂŶĚtĞƐƚƉŚĂů,͘'ĚŶĨŚĂƉůŽŝŶƐƵĨĨŝĐŝĞŶĐLJĐĂƵƐĞƐ ,ŝƌƐĐŚƐƉƌƵŶŐͲůŝŬĞŝŶƚĞƐƚŝŶĂůŽďƐƚƌƵĐƚŝŽŶĂŶĚĞĂƌůLJͲŽŶƐĞƚůĞƚŚĂůŝƚLJŝŶŵŝĐĞ͘ŵ:,Ƶŵ'ĞŶĞƚ͘ϮϬϬϮ͖ϳϬ͗ϰϯϱͲϰϳ͘ ϭϳ͘ DƵƐƐĞƌD͕ŽƌƌĞĂ,ĂŶĚ^ŽƵƚŚĂƌĚͲ^ŵŝƚŚD͘ŶƚĞƌŝĐŶĞƵƌŽŶŝŵďĂůĂŶĐĞĂŶĚƉƌŽdžŝŵĂůĚLJƐŵŽƚŝůŝƚLJŝŶ ŐĂŶŐůŝŽŶĂƚĞĚŝŶƚĞƐƚŝŶĞŽĨƚŚĞ,ŝƌƐĐŚƐƉƌƵŶŐŵŽƵƐĞŵŽĚĞů͘ĞůůƵůĂƌĂŶĚŵŽůĞĐƵůĂƌŐĂƐƚƌŽĞŶƚĞƌŽůŽŐLJĂŶĚ ŚĞƉĂƚŽůŽŐLJ͘ϮϬϭϱ͖ϭ͗ϴϳͲϭϬϭ͘ ϭϴ͘ ĞƌŐĞƌŽŶ<&͕ĂƌĚŝŶĂůd͕dŽƵƌĞD͕ĞƚĂů͘DĂůĞͲŝĂƐĞĚŐĂŶŐůŝŽŶŝĐDĞŐĂĐŽůŽŶŝŶƚŚĞdĂƐŚdDŽƵƐĞ>ŝŶĞ ƵĞƚŽWĞƌƚƵƌďĂƚŝŽŶŽĨ^ŝůĞŶĐĞƌůĞŵĞŶƚƐŝŶĂ>ĂƌŐĞ'ĞŶĞĞƐĞƌƚŽĨŚƌŽŵŽƐŽŵĞϭϬ͘W>Ž^'ĞŶĞƚ͘ϮϬϭϱ͖ϭϭ͗ ĞϭϬϬϱϬϵϯ͘ ϭϵ͘ ŶŽŵŽƚŽ,͕ƌĂŬŝd͕:ĂĐŬŵĂŶ͕ĞƚĂů͘'&ZĂůƉŚĂϭͲĚĞĨŝĐŝĞŶƚŵŝĐĞŚĂǀĞĚĞĨŝĐŝƚƐŝŶƚŚĞĞŶƚĞƌŝĐŶĞƌǀŽƵƐ ƐLJƐƚĞŵĂŶĚŬŝĚŶĞLJƐ͘EĞƵƌŽŶ͘ϭϵϵϴ͖Ϯϭ͗ϯϭϳͲϮϰ͘ ϮϬ͘ ,ĂƚnjŝƉĞƚƌŽƐd͕ŽŐĚĂŶŝŬ>W͕dĂƐƐŝŶĂƌŝsZ͕ĞƚĂů͘ϱϳ>ͬϲ:ĐŽŶŐĞŶŝĐWƌƉͲdWϰϯϯϭϱdŵŝĐĞĚĞǀĞůŽƉ ƉƌŽŐƌĞƐƐŝǀĞŶĞƵƌŽĚĞŐĞŶĞƌĂƚŝŽŶŝŶƚŚĞŵLJĞŶƚĞƌŝĐƉůĞdžƵƐŽĨƚŚĞĐŽůŽŶǁŝƚŚŽƵƚĞdžŚŝďŝƚŝŶŐŬĞLJĨĞĂƚƵƌĞƐŽĨ>^͘ ƌĂŝŶZĞƐ͘ϮϬϭϰ͖ϭϱϴϰ͗ϱϵͲϳϮ͘. r ee rP Fo. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 18 of 42.

(121) Page 19 of 42. dŽƵƌĠϭϵ  Ϯϭ͘ <ŝŵďĂůů^͕WĂůŵĞƌ:D͕ΖŶĚƌĞĂDZ͕,ŽƌŶďLJW:ĂŶĚtĂĚĞWZ͘ĐƵƚĞĐŽůŝƚŝƐŝŶĚƵĐƚŝŽŶďLJŽŝůŽĨŵƵƐƚĂƌĚ ƌĞƐƵůƚƐŝŶůĂƚĞƌĚĞǀĞůŽƉŵĞŶƚŽĨĂŶ/^ͲůŝŬĞĂĐĐĞůĞƌĂƚĞĚƵƉƉĞƌ'/ƚƌĂŶƐŝƚŝŶŵŝĐĞ͘ŵ:WŚLJƐŝŽů'ĂƐƚƌŽŝŶƚĞƐƚ>ŝǀĞƌ WŚLJƐŝŽů͘ϮϬϬϱ͖Ϯϴϴ͗'ϭϮϲϲͲϳϯ͘ ϮϮ͘ >ŝ͕ŚĂůĂnjŽŶŝƚŝƐ͕,ƵĂŶŐzz͕ĞƚĂů͘ƐƐĞŶƚŝĂůƌŽůĞƐŽĨĞŶƚĞƌŝĐŶĞƵƌŽŶĂůƐĞƌŽƚŽŶŝŶŝŶŐĂƐƚƌŽŝŶƚĞƐƚŝŶĂů ŵŽƚŝůŝƚLJĂŶĚƚŚĞĚĞǀĞůŽƉŵĞŶƚͬƐƵƌǀŝǀĂůŽĨĞŶƚĞƌŝĐĚŽƉĂŵŝŶĞƌŐŝĐŶĞƵƌŽŶƐ͘:EĞƵƌŽƐĐŝ͘ϮϬϭϭ͖ϯϭ͗ϴϵϵϴͲϵϬϬϵ͘ Ϯϯ͘ tĂůůĂĐĞ^͕dĂŶDy͕^ĐŚĂĐŚŶĞƌDĂŶĚŶĚĞƌƐŽŶZ͘>ϭĐĂŵĂĐƚƐĂƐĂŵŽĚŝĨŝĞƌŐĞŶĞĨŽƌŵĞŵďĞƌƐŽĨƚŚĞ ĞŶĚŽƚŚĞůŝŶƐŝŐŶĂůůŝŶŐƉĂƚŚǁĂLJĚƵƌŝŶŐĞŶƚĞƌŝĐŶĞƌǀŽƵƐƐLJƐƚĞŵĚĞǀĞůŽƉŵĞŶƚ͘EĞƵƌŽŐĂƐƚƌŽĞŶƚĞƌŽůDŽƚŝů͘ϮϬϭϭ͖ Ϯϯ͗ĞϱϭϬͲϮϮ͘ Ϯϰ͘ ^ŽƌĞƚZ͕DĞŶŶĞƚƌĞLJD͕ĞƌŐĞƌŽŶ<&͕ĞƚĂů͘ĐŽůůĂŐĞŶs/ͲĚĞƉĞŶĚĞŶƚƉĂƚŚŽŐĞŶŝĐŵĞĐŚĂŶŝƐŵĨŽƌ ,ŝƌƐĐŚƐƉƌƵŶŐΖƐĚŝƐĞĂƐĞ͘:ůŝŶ/ŶǀĞƐƚ͘ϮϬϭϱ͖ϭϮϱ͗ϰϰϴϯͲϵϲ͘ Ϯϱ͘ tĂƌĚ^D͕KƌĚŽŐd͕ĂLJŐƵŝŶŽǀ:Z͕ĞƚĂů͘ĞǀĞůŽƉŵĞŶƚŽĨŝŶƚĞƌƐƚŝƚŝĂůĐĞůůƐŽĨĂũĂůĂŶĚƉĂĐĞŵĂŬŝŶŐŝŶ ŵŝĐĞůĂĐŬŝŶŐĞŶƚĞƌŝĐŶĞƌǀĞƐ͘'ĂƐƚƌŽĞŶƚĞƌŽůŽŐLJ͘ϭϵϵϵ͖ϭϭϳ͗ϱϴϰͲϵϰ͘ Ϯϲ͘ ,ƵŝnjŝŶŐĂ:͕ĞƌĞnjŝŶ/͕^ŝƌĐĂƌ<͕ĞƚĂů͘ĞǀĞůŽƉŵĞŶƚŽĨŝŶƚĞƌƐƚŝƚŝĂůĐĞůůƐŽĨĂũĂůŝŶĂĨƵůůͲƚĞƌŵŝŶĨĂŶƚ ǁŝƚŚŽƵƚĂŶĞŶƚĞƌŝĐŶĞƌǀŽƵƐƐLJƐƚĞŵ͘'ĂƐƚƌŽĞŶƚĞƌŽůŽŐLJ͘ϮϬϬϭ͖ϭϮϬ͗ϱϲϭͲϳ͘ Ϯϳ͘ ,ƵŝnjŝŶŐĂ:͕ĂƌĂƚĞEĂŶĚ&ĂƌƌƵŐŝĂ'͘WŚLJƐŝŽůŽŐLJ͕ŝŶũƵƌLJ͕ĂŶĚƌĞĐŽǀĞƌLJŽĨŝŶƚĞƌƐƚŝƚŝĂůĐĞůůƐŽĨĂũĂů͗ďĂƐŝĐ ĂŶĚĐůŝŶŝĐĂůƐĐŝĞŶĐĞ͘'ĂƐƚƌŽĞŶƚĞƌŽůŽŐLJ͘ϮϬϬϵ͖ϭϯϳ͗ϭϱϰϴͲϱϲ͘ Ϯϴ͘ ^ĂŶĚŐƌĞŶ<͕>ĂƌƐƐŽŶ>dĂŶĚŬďůĂĚ͘tŝĚĞƐƉƌĞĂĚĐŚĂŶŐĞƐŝŶŶĞƵƌŽƚƌĂŶƐŵŝƚƚĞƌĞdžƉƌĞƐƐŝŽŶĂŶĚŶƵŵďĞƌ ŽĨĞŶƚĞƌŝĐŶĞƵƌŽŶƐĂŶĚŝŶƚĞƌƐƚŝƚŝĂůĐĞůůƐŽĨĂũĂůŝŶůĞƚŚĂůƐƉŽƚƚĞĚŵŝĐĞ͗ĂŶĞdžƉůĂŶĂƚŝŽŶĨŽƌƉĞƌƐŝƐƚŝŶŐĚLJƐŵŽƚŝůŝƚLJ ĂĨƚĞƌŽƉĞƌĂƚŝŽŶĨŽƌ,ŝƌƐĐŚƐƉƌƵŶŐΖƐĚŝƐĞĂƐĞ͍ŝŐŝƐ^Đŝ͘ϮϬϬϮ͖ϰϳ͗ϭϬϰϵͲϲϰ͘ Ϯϵ͘ ΖƵƚƌĞĂƵdž&͕DĂƌŐŽůŝƐ<'͕ZŽďĞƌƚƐ:͕ĞƚĂů͘džƉƌĞƐƐŝŽŶůĞǀĞůŽĨ,ĂŶĚϮĂĨĨĞĐƚƐƐƉĞĐŝĨŝĐĂƚŝŽŶŽĨĞŶƚĞƌŝĐ ŶĞƵƌŽŶƐĂŶĚŐĂƐƚƌŽŝŶƚĞƐƚŝŶĂůĨƵŶĐƚŝŽŶŝŶŵŝĐĞ͘'ĂƐƚƌŽĞŶƚĞƌŽůŽŐLJ͘ϮϬϭϭ͖ϭϰϭ͗ϱϳϲͲϴϳ͕ϴϳĞϭͲϲ͘ ϯϬ͘ tƌŝŐŚƚͲ:ŝŶ͕'ƌŝĚĞƌ:Z͕ƵĞƐƚĞƌ'ĂŶĚ,ĞƵĐŬĞƌŽƚŚZK͘ZĞƚŝŶĂůĚĞŚLJĚĞĚĞŚLJĚƌŽŐĞŶĂƐĞĞŶnjLJŵĞƐ ƌĞŐƵůĂƚĞĐŽůŽŶĞŶƚĞƌŝĐŶĞƌǀŽƵƐƐLJƐƚĞŵƐƚƌƵĐƚƵƌĞĂŶĚĨƵŶĐƚŝŽŶ͘ĞǀŝŽů͘ϮϬϭϯ͖ϯϴϭ͗ϮϴͲϯϳ͘ ϯϭ͘ YƵ͕dŚĂĐŬĞƌD͕ĂƐƚĞůƵĐĐŝW͕ĂŐLJĂŶƐnjŬŝD͕ƉƐƚĞŝŶD>ĂŶĚ&ƵƌŶĞƐƐ:͘/ŵŵƵŶŽŚŝƐƚŽĐŚĞŵŝĐĂů ĂŶĂůLJƐŝƐŽĨŶĞƵƌŽŶƚLJƉĞƐŝŶƚŚĞŵŽƵƐĞƐŵĂůůŝŶƚĞƐƚŝŶĞ͘ĞůůdŝƐƐƵĞZĞƐ͘ϮϬϬϴ͖ϯϯϰ͗ϭϰϳͲϲϭ͘ ϯϮ͘ ĂŝƚŽƵŶ/͕ƌŝĐŬƐŽŶ^͕ĂƌůŽǁ:͕ĞƚĂů͘ůƚĞƌĞĚŶĞƵƌŽŶĂůĚĞŶƐŝƚLJĂŶĚŶĞƵƌŽƚƌĂŶƐŵŝƚƚĞƌĞdžƉƌĞƐƐŝŽŶŝŶƚŚĞ ŐĂŶŐůŝŽŶĂƚĞĚƌĞŐŝŽŶŽĨĚŶƌďŶƵůůŵŝĐĞ͗ŝŵƉůŝĐĂƚŝŽŶƐĨŽƌ,ŝƌƐĐŚƐƉƌƵŶŐΖƐĚŝƐĞĂƐĞ͘EĞƵƌŽŐĂƐƚƌŽĞŶƚĞƌŽůDŽƚŝů͘ ϮϬϭϯ͖Ϯϱ͗ĞϮϯϯͲϰϰ͘ ϯϯ͘ ŶĚĞƌƐŽŶZ͕^ƚĞǁĂƌƚ>ĂŶĚzŽƵŶŐ,D͘WŚĞŶŽƚLJƉĞƐŽĨŶĞƵƌĂůͲĐƌĞƐƚͲĚĞƌŝǀĞĚĐĞůůƐŝŶǀĂŐĂůĂŶĚƐĂĐƌĂů ƉĂƚŚǁĂLJƐ͘ĞůůdŝƐƐƵĞZĞƐ͘ϮϬϬϲ͖ϯϮϯ͗ϭϭͲϮϱ͘ ϯϰ͘ hĞƐĂŬĂdĂŶĚŶŽŵŽƚŽ,͘EĞƵƌĂůƉƌĞĐƵƌƐŽƌĚĞĂƚŚŝƐĐĞŶƚƌĂůƚŽƚŚĞƉĂƚŚŽŐĞŶĞƐŝƐŽĨŝŶƚĞƐƚŝŶĂů ĂŐĂŶŐůŝŽŶŽƐŝƐŝŶZĞƚŚLJƉŽŵŽƌƉŚŝĐŵŝĐĞ͘:EĞƵƌŽƐĐŝ͘ϮϬϭϬ͖ϯϬ͗ϱϮϭϭͲϴ͘ ϯϱ͘ tĂŶŐ,͕,ƵŐŚĞƐ/͕WůĂŶĞƌt͕ĞƚĂů͘dŚĞƚŝŵŝŶŐĂŶĚůŽĐĂƚŝŽŶŽĨŐůŝĂůĐĞůůůŝŶĞͲĚĞƌŝǀĞĚŶĞƵƌŽƚƌŽƉŚŝĐĨĂĐƚŽƌ ĞdžƉƌĞƐƐŝŽŶĚĞƚĞƌŵŝŶĞĞŶƚĞƌŝĐŶĞƌǀŽƵƐƐLJƐƚĞŵƐƚƌƵĐƚƵƌĞĂŶĚĨƵŶĐƚŝŽŶ͘:EĞƵƌŽƐĐŝ͘ϮϬϭϬ͖ϯϬ͗ϭϱϮϯͲϯϴ͘ ϯϲ͘ zĂŶ,͕ĞƌŐŶĞƌ:͕ŶŽŵŽƚŽ,͕DŝůďƌĂŶĚƚ:͕EĞǁŐƌĞĞŶ&ĂŶĚzŽƵŶŐ,D͘EĞƵƌĂůĐĞůůƐŝŶƚŚĞĞƐŽƉŚĂŐƵƐ ƌĞƐƉŽŶĚƚŽŐůŝĂůĐĞůůůŝŶĞͲĚĞƌŝǀĞĚŶĞƵƌŽƚƌŽƉŚŝĐĨĂĐƚŽƌĂŶĚŶĞƵƌƚƵƌŝŶ͕ĂŶĚĂƌĞZdͲĚĞƉĞŶĚĞŶƚ͘ĞǀŝŽů͘ϮϬϬϰ͖ ϮϳϮ͗ϭϭϴͲϯϯ͘. r ee rP Fo. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility.  . .

(122) Neurogastroenterology and Motility. dŽƵƌĠϮϬ . ),*85(/(*(1'6 )LJXUH)HFDOUHWHQWLRQLQWKHFRORQRIDGXOW7DVK7 FRORQV IURP DGXOW ZLOGW\SH DQG 7DVK7. 7J7J. PDOHV $

(123) 5HSUHVHQWDWLYHLPDJHVRIZKROH. 7J7J.  PLFH 1XPEHUV DUH DUELWUDU\ XQLWV $8

(124)  DVVLJQHG E\. VRPHRQHZKRZDVEOLQGHGWRJHQRW\SHLQRUGHU WRJUDGHIHFDOLPSDFWLRQZHOOVHSDUDWHGSHOOHWVDV REVHUYHGLQWKHFRORQRIZLOGW\SHPLFH DUURZKHDGV

(125) DQGVPDOODQGKLJKQXPEHUVRIFRPSDFWHG IHFHV UHVSHFWLYHO\ DUURZV

(126)  1RWH WKDW 7DVK7. 7J7J.  PDOHV GLVSOD\ PDUNHGO\ KLJKHU IHFDO LPSDFWLRQ LQ. FRPSDULVRQWR7DVK77J7J IHPDOHVDQGZLOGW\SHFRQWUROV %

(127) 4XDQWLWDWLYHDQDO\VHVXVLQJWKHDUELWUDU\. r ee rP Fo. XQLWVGHVFULEHGLQ$ S”6WXGHQW¶VWWHVW

(128)  . )LJXUH  ,PSDLUHG JDVWURLQWHVWLQDO *,

(129)  PRWLOLW\ LQ DGXOW 7DVK77J7J PDOHV $

(130)  7RWDO *, WUDQVLW HYDOXDWHG E\ WKH WLPH KRXUPLQXWHV

(131)  UHTXLUHG IRU H[SHOOLQJ WKH ILUVW UHG SHOOHW IROORZLQJ RUDO JDYDJH ZLWKFDUPLQHUHGG\H1RWHWKDWWKHDYHUDJHWLPHRIWRWDO*,WUDQVLWLVLQFUHDVHGLQ7DVK77J7JPDOHVLQ. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 20 of 42. FRPSDULVRQ WR 7DVK77J7J IHPDOHV DQG ZLOGW\SH FRQWUROV %

(132)  3UR[LPDO *, WUDQVLW HYDOXDWHG E\ WKH GLVWDQFHWUDYHOHGE\WKHFDUPLQHUHGG\HPLQDIWHUJDYDJHDQGH[SUHVVHGLQSHUFHQWDJHRIWKHWRWDO OHQJWKRIWKHVPDOOLQWHVWLQH &

(133) 'LVWDOFRORQLFWUDQVLWHYDOXDWHGE\EHDGODWHQF\DVVD\DQGH[SUHVVHGLQ PLQ 1RWH WKDW WKH DYHUDJH WLPH RI GLVWDO FRORQLF WUDQVLW LQ 7DVK77J7J PDOHV LV IROG JUHDWHU LQ FRPSDULVRQWR7DVK77J7JIHPDOHVDQGZLOGW\SHFRQWUROV S” S”6WXGHQW¶VWWHVW

(134)   )LJXUH  $GXOW 7DVK77J7J PLFH H[KLELW PDOHELDVHG VKRUWVHJPHQW DJDQJOLRQRVLV DQG K\SRJDQJOLRQRVLV $

(135) 5HSUHVHQWDWLYHLPDJHVRIZKROHPRXQWVWDLQLQJRIDFHW\OFKROLQHVWHUDVHDFWLYLW\ LQWKHP\HQWHULFSOH[XVRIDGXOWZLOGW\SHDQG7DVK77J7JPLFH1RWHWKDWDOO7DVK77J7JDQLPDOVH[KLELW K\SRJDQJOLRQRVLVLQWKHPLGFRORQZKHUHDVHLWKHUK\SRJDQJOLRQRVLVRUDJDQJOLRQRVLVLVREVHUYHGLQWKH GLVWDOFRORQ$UURZDQGDUURZKHDGVLQGLFDWHP\HQWHULFJDQJOLDDQGH[WULQVLFQHUYHILEHUVUHVSHFWLYHO\.

(136) Page 21 of 42. dŽƵƌĠϮϭ . 6FDOH EDU PP %

(137)  4XDQWLILFDWLRQ RI WKH H[WHQW RI DJDQJOLRQRVLV H[SUHVVHG LQ SHUFHQWDJH RI WRWDO FRORQ OHQJWK 7KH DYHUDJH H[WHQW RI DJDQJOLRQRVLV LV VLJQLILFDQWO\ LQFUHDVHG LQ 7DVK77J7J PDOHV FRPSDUHG WR IHPDOHV &

(138)  4XDQWLWDWLYH DQDO\VLV RI P\HQWHULF SOH[XV GHQVLW\ LQ JDQJOLRQDWHG UHJLRQV XVLQJLPDJHVVLPLODUWRWKRVHVKRZQLQ $

(139) WDNHQIURPWKHSUR[LPDOPLGDQGGLVWDOPLGFRORQ 0&

(140)  DQGIURPWKHSUR[LPDODQGPLGGLVWDOFRORQ '&

(141) 1RWHWKDWWKHDJDQJOLRQLFGLVWDO'&ZDVQRWLQFOXGHG IRUWKHVHDQDO\VHV7KHDUHDRFFXSLHGE\WKHP\HQWHULFSOH[XVZDVPHDVXUHGIURPUHSUHVHQWDWLYHILHOGV RIYLHZDQGH[SUHVVHGLQSHUFHQWDJHRIWKHWRWDODUHDRIWKHILHOGRIYLHZ PP

(142) (DFKVLQJOHYDOXH. r ee rP Fo. FRUUHVSRQGVWRWKHDYHUDJHRIHLWKHUWKUHH SUR[LPDOPLGDQGGLVWDO0&

(143) RUWZR SUR[LPDODQGPLG'&

(144)  VXEUHJLRQV XVLQJ RQH UHSUHVHQWDWLYH ILHOG RI YLHZ SHU VXEUHJLRQ

(145)  '

(146)  4XDQWLWDWLYH DQDO\VHV RI DQWL +X&' LPPXQRIOXRUHVFHQFH GDWD LQ JDQJOLRQDWHG UHJLRQV RI 7DVK77J7J FRORQV XVLQJ LPDJHV VXFK DV WKRVHVKRZQLQ6XSSOHPHQWDO)LJXUHWDNHQIURPWKHSUR[LPDO0&DQGPLG'&)RUHDFKVXEUHJLRQ WKH P\HQWHULF QHXURQDO GHQVLW\ ZDV FDOFXODWHG IURP  ILHOGV RI YLHZ DQG H[SUHVVHG LQ QXPEHU RI +X&' FHOOV SHU PP 1RWH WKDW D VLJQLILFDQW GHFUHDVH RI P\HQWHULF SOH[XV GHQVLW\ DQG QHXURQ. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility. QXPEHUVLVREVHUYHGLQ7DVK77J7JPLFHRIERWKJHQGHUVEXWLVPRUHSURQRXQFHGLQPDOHV S” S” S”6WXGHQW¶VWWHVW

(147)  . )LJXUH  &RUUHODWLRQ EHWZHHQ GLVWDO FRORQLF WUDQVLW WLPH DQG H[WHQW RI K\SRJDQJOLRQRVLV RU DJDQJOLRQRVLVH[KLELWHGE\DGXOW7DVK77J7JPLFH $

(148) 3ORWRIGLVWDOFRORQLFWUDQVLWWLPH )LJXUH&

(149)  UHODWLYH WR DYHUDJH P\HQWHULF SOH[XV GHQVLW\ LQ WKH GLVWDO FRORQ FRPELQLQJ SUR[LPDO DQG PLG EXW H[FOXGLQJ GLVWDO VXEUHJLRQV

(150)  RI ³K\SRJDQJOLRQLF´ 7DVK77J7J PLFH )LJXUH &

(151)  'LVWDO FRORQLF WUDQVLW WLPH WHQGV WR EH LQYHUVHO\ FRUUHODWHG WR P\HQWHULF SOH[XV GHQVLW\ EXW RQO\ IRU 7DVK77J7J PDOHV %

(152)  3ORW RI GLVWDO FRORQLF WUDQVLW WLPH )LJXUH &

(153)  UHODWLYH WR WKH H[WHQW RI FRORQLF DJDQJOLRQRVLV LQ ³DJDQJOLRQLF´7DVK77J7JPDOHV )LJXUH%

(154) 2QO\ DPRGHUDWHSRVLWLYHFRUUHODWLRQWKDWGRHVQRWUHDFK VWDWLVWLFDOVLJQLILFDQFHLVREVHUYHGU3HDUVRQ¶VFRUUHODWLRQFRHIILFLHQWS6WXGHQW¶VWWHVWYDOXH.

(155) Neurogastroenterology and Motility. dŽƵƌĠϮϮ .  )LJXUH7KHSURSRUWLRQRI&DOUHWLQLQP\HQWHULFQHXURQVLVXQDIIHFWHGLQDGXOW7DVK77J7JPLFH $%

(156) 5HSUHVHQWDWLYH=SURMHFWLRQPLFURJUDSKVRIP\HQWHULFJDQJOLDIURPWKHPLG'&RIPDOH $

(157) DQG IHPDOH %

(158)  PLFH GRXEOHODEHOOHG ZLWK DQWL&DOUHWLQLQ JUHHQ

(159)  DQG DQWL+X&' UHG

(160)  DQWLERGLHV  6FDOH EDU—P $¶%¶

(161) 4XDQWLWDWLYHDQDO\VHVRIWKHDYHUDJHSURSRUWLRQRI&DOUHWLQLQP\HQWHULFQHXURQVLQ WKHGXRGHQXPDQGPLG'&1RVWDWLVWLFDOO\VLJQLILFDQWGLIIHUHQFHLVREVHUYHGEHWZHHQ7DVK77J7J PLFH DQGDJHDQGJHQGHUPDWFKHGFRQWUROV'&GLVWDOFRORQ. r ee rP Fo. . )LJXUH0DOHVSHFLILFDQGUHJLRQDOO\UHVWULFWHGLQFUHDVHRIQ1RVQHXURQQXPEHUVLQP\HQWHULF JDQJOLD RI DGXOW 7DVK77J7J PLFH $%

(162)  5HSUHVHQWDWLYH = SURMHFWLRQ PLFURJUDSKV RI P\HQWHULF JDQJOLDIURPWKHPLG'&RIPDOH $

(163) DQGIHPDOH %

(164) PLFHGRXEOHODEHOOHGZLWKDQWLQ1RV JUHHQ

(165) DQG DQWL+X&' UHG

(166) DQWLERGLHV6FDOHEDU—P $¶%¶

(167) 4XDQWLWDWLYHDQDO\VHVRIWKHDYHUDJHSURSRUWLRQ RIQ1RVP\HQWHULFQHXURQVLQWKHGXRGHQXPDQGPLG'&7KHDYHUDJHSURSRUWLRQRIQ1RVP\HQWHULF. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 22 of 42. QHXURQVLVVSHFLILFDOO\LQFUHDVHGLQWKHPLG'&RI7DVK77J7JPDOHV S”6WXGHQW¶VWWHVW

(168) '& GLVWDOFRORQ . 6XSSOHPHQWDO)LJXUH,OOXVWUDWLRQRIDPRXVHJDVWURLQWHVWLQDOWUDFWVKRZLQJWKHSRVLWLRQRIWKH VXEUHJLRQVWKDWZHUHXVHGLQWKLVVWXG\  6XSSOHPHQWDO)LJXUH&RPSOHWHYLVXDODQDO\VLVRIIHFDOLPSDFWLRQLQ7DVK77J7JPLFH$OOFRORQV IURP DGXOW 7DVK7. 7J7J.  PLFH XVHG WR TXDQWLI\ IHFDO LPSDFWLRQ LQ )LJXUH % DUH VKRZQ DORQJ ZLWK. UHSUHVHQWDWLYHLPDJHVRIFRQWUROFRORQV.

(169) Page 23 of 42. dŽƵƌĠϮϯ .  6XSSOHPHQWDO )LJXUH  &RORQLF GLVWHQWLRQ FDQQRW H[SODLQ WKH UREXVW GHFUHDVH LQ P\HQWHULF SOH[XVGHQVLW\GLVSOD\HGE\DGXOW7DVK77J7JPDOHV3ORWRI0&ZLGWK FRPELQLQJSUR[LPDOPLGDQG GLVWDOVXEUHJLRQV

(170) UHODWLYHWRFRUUHVSRQGLQJP\HQWHULFSOH[XVGHQVLW\RIDGXOWZLOGW\SHDQG7DVK77J7J PDOH PLFH Q  DQLPDOV IRU HDFK

(171)  (DFK VLQJOH YDOXH FRUUHVSRQGV WR DQ LQGLYLGXDO VXEUHJLRQ 1R FRUUHODWLRQ LV REVHUYHG EHWZHHQ WKH FRORQ ZLGWK DQG WKH P\HQWHULF SOH[XV GHQVLW\ IRU ERWK ZLOGW\SH DQG7DVK77J7JPLFH U3HDUVRQ¶VFRHIILFLHQWS6WXGHQW¶VWWHVWYDOXH

(172) 0&PLGFRORQ . r ee rP Fo. 6XSSOHPHQWDO )LJXUH  0DOHELDVHG UHGXFHG P\HQWHULF QHXURQDO GHQVLW\ LQ WKH FRORQ RI DGXOW 7DVK77J7JPLFH $

(173) 5HSUHVHQWDWLYH=SURMHFWLRQPLFURJUDSKVRIP\HQWHULFQHXURQVIURPWKHSUR[LPDO 0&DQGPLG'&RIDGXOWZLOGW\SHDQG7DVK77J7JPDOHVODEHOOHGZLWKDQDQWL+X&' JUH\

(174) DQWLERG\ 6FDOH EDU —P %

(175)  4XDQWLWDWLYH DQDO\VHV RI P\HQWHULF QHXURQ QXPEHUV LQ SUR[LPDO 0& DQG PLG '& 7KH DYHUDJH QXPEHU RI P\HQWHULF QHXURQV LV UHGXFHG LQ DOO 7DVK77J7J PLFH DQ RXWFRPH WKDW. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility. DSSHDUVPRUHSURQRXQFHGLQPDOHV S” S”6WXGHQW¶VWWHVW

(176) 0&PLGFRORQ'& GLVWDOFRORQ . 6XSSOHPHQWDO)LJXUH7KHP\HQWHULFQHXURQDOGHQVLW\LVXQDIIHFWHGLQWKHGXRGHQXPRIDGXOW 7DVK77J7J PLFH $%

(177)  5HSUHVHQWDWLYH = SURMHFWLRQ PLFURJUDSKV RI P\HQWHULF QHXURQV IURP WKH GXRGHQXP RI DGXOW ZLOGW\SH DQG 7DVK77J7J PDOHV $

(178)  RU IHPDOHV %

(179)  ODEHOOHG ZLWK DQ DQWL+X&' JUH\

(180) DQWLERG\6FDOHEDU—P $¶%¶

(181) 4XDQWLWDWLYHDQDO\VHVRIP\HQWHULFQHXURQQXPEHUVLQWKH GXRGHQXP 7KH DYHUDJH QHXURQDO GHQVLW\ LV FRPSDUDEOH EHWZHHQ 7DVK77J7J DQG DJH DQG JHQGHU PDWFKHGZLOGW\SHPLFH .

(182) Neurogastroenterology and Motility. dŽƵƌĠϮϰ . 6XSSOHPHQWDO )LJXUH  ,QWHUJHQGHU FRPSDUDWLYH DQDO\VHV RI P\HQWHULF SOH[XV GHQVLW\ DQG QHXURQ QXPEHUV LQ DJHPDWFKHG 7DVK77J7J PLFH $

(183)  7KH DYHUDJH P\HQWHULF SOH[XV GHQVLW\ DV GHWHUPLQHG XVLQJ $&K( KLVWRFKHPLVWU\ LV VLJQLILFDQWO\ UHGXFHG LQ 7DVK77J7J PDOHV FRPSDUHG WR IHPDOHV $V GHVFULEHG LQ )LJXUH & HDFK VLQJOH YDOXH LQ 0& DQG '& FRUUHVSRQGV WR WKH DYHUDJH RI WKUHH RU WZR VXEUHJLRQVUHVSHFWLYHO\ %

(184) 7KHDYHUDJHQXPEHURI+X&'QHXURQVSHUPPLVVPDOOHULQ7DVK77J7J PDOHV UHODWLYH WR IHPDOHV S ”  S ”  S ”  6WXGHQW¶V WWHVW

(185)  0& PLG FRORQ '&GLVWDOFRORQ . r ee rP Fo. 6XSSOHPHQWDO)LJXUH7KHQHXURQJOLDUDWLRZLWKLQP\HQWHULFJDQJOLDLVXQFKDQJHGLQWKHGLVWDO FRORQ RI DGXOW 7DVK77J7J PLFH $

(186)  5HSUHVHQWDWLYH = SURMHFWLRQ PLFURJUDSKV RI P\HQWHULF JDQJOLD IURPWKHSUR[LPDODQGPLG'&RIDGXOWZLOGW\SHDQG7DVK77J7JPLFHGRXEOHODEHOOHGZLWKDQWL6R[ JUHHQ

(187)  DQG DQWL+X&' UHG

(188)  DQWLERGLHV 6FDOH EDU —P %

(189)  4XDQWLWDWLYH DQDO\VHV RI WKH QHXURQJOLD UDWLR LQ ZLOGW\SH DQG 7DVK77J7J PLFH RI ERWK JHQGHUV 1R VWDWLVWLFDOO\ VLJQLILFDQW. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 24 of 42. GLIIHUHQFH LV REVHUYHG EHWZHHQ 7DVK77J7J PLFH DQG DJH DQG JHQGHUPDWFKHG FRQWUROV '& GLVWDO FRORQ . 6XSSOHPHQWDO )LJXUH  7KH SURSRUWLRQ RI Q1RV P\HQWHULF QHXURQV LV XQDIIHFWHG LQ WKH K\SRJDQJOLRQLF '& RIDGXOW 7DVK77J7JIHPDOHV $%

(190)  5HSUHVHQWDWLYH = SURMHFWLRQ PLFURJUDSKV RI P\HQWHULF JDQJOLD IURP WKH GLVWDO '& RI DJHPDWFKHG ZLOGW\SH DQG 7DVK77J7J IHPDOH PLFH ODEHOOHG ZLWKDQWL+X&' UHG

(191) DQGDQWLQ1RV JUHHQ

(192) DQWLERGLHV $

(193) RUZLWKDQWL+X&' JUH\

(194) RQO\ %

(195) 6FDOH EDUV —P $

(196)  DQG —P %

(197)  $¶%¶

(198)  4XDQWLWDWLYH DQDO\VHV RI WKH DYHUDJH SURSRUWLRQ RI Q1RV P\HQWHULFQHXURQVDQGWKHDYHUDJHQHXURQDOGHQVLW\LQWKHGLVWDO'&7KHDYHUDJHSURSRUWLRQRIQ1RV.

(199) Page 25 of 42. dŽƵƌĠϮϱ . P\HQWHULFQHXURQVLVFRPSDUDEOHEHWZHHQZLOGW\SHDQG7DVK77J7JIHPDOHV $¶

(200) GHVSLWHDVLJQLILFDQW GHFUHDVHLQWKHDYHUDJHQHXURQDOGHQVLW\ %¶

(201)  S”6WXGHQW¶VWWHVW

(202) '&GLVWDOFRORQ  6XSSOHPHQWDO)LJXUH7KHSURSRUWLRQRIQ1RVP\HQWHULFQHXURQVLVQRWDOWHUHGLQWKHSUR[LPDO 0& RI DGXOW 7DVK77J7J PDOHV $

(203)  5HSUHVHQWDWLYH = SURMHFWLRQ PLFURJUDSKV RI P\HQWHULF JDQJOLD IURPWKHSUR[LPDO0&RIDJHPDWFKHGZLOGW\SHDQG7DVK77J7JPDOHPLFHGRXEOHODEHOOHGZLWKDQWL Q1RV JUHHQ

(204)  DQG DQWL+X&' UHG

(205)  DQWLERGLHV 6FDOH EDU —P %

(206)  4XDQWLWDWLYH DQDO\VHV RI WKH. r ee rP Fo. DYHUDJH SURSRUWLRQ RI Q1RV P\HQWHULF QHXURQV LQ WKH SUR[LPDO 0& 1R GLIIHUHQFH LV REVHUYHG EHWZHHQZLOGW\SHDQG7DVK77J7JPLFH0&PLGFRORQ . 6XSSOHPHQWDO)LJXUH'LVWULEXWLRQRILQWHUVWLWLDOFHOOVRI&DMDO ,&&

(207) LQK\SRJDQJOLRQLFGLVWDO '& RI DGXOW 7DVK77J7J PLFH5HSUHVHQWDWLYH = SURMHFWLRQ PLFURJUDSKV RI ,&& DV ZHOO DV P\HQWHULF. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility. DQG GHHS PXVFXODULV QHXURQDO SOH[XVHV IURP WKH GLVWDO '& RI DGXOW ZLOGW\SH DQG 7DVK77J7J PLFH ODEHOHGZLWKDQWLF.LW JUHHQ

(208) DQGDQWLȕ,,,7XEXOLQ UHG

(209) UHVSHFWLYHO\,&&/0DQG,&&&0DUH,&& ORFDWHG ZLWKLQ WKH ORQJLWXGLQDO DQG FLUFXODU VPRRWK PXVFOH OD\HUV UHVSHFWLYHO\ ,&&0< DQG ,&& '03DUH,&&SUHVHQWDWWKHOHYHORIWKHP\HQWHULFDQGWKHGHHSPXVFXODULVSOH[XVHVUHVSHFWLYHO\1R RYHUWFKDQJHLVGHWHFWHGLQWKHGLVWULEXWLRQRIWKHVHGLIIHUHQW,&&VXESRSXODWLRQVEHWZHHQDGXOWZLOG W\SHDQG7DVK77J7JPLFH6FDOHEDU—P. .

(210) Neurogastroenterology and Motility. dŽƵƌĠϮϲ . 7DEOH&RPSDULVRQRIERG\ZHLJKWEHWZHHQZLOGW\SHDQG7DVK7 PRQWKV *HQGHU. *HQRW\SH.    .  . Ƃ.    . PLFHDW33DQG. 3. 3. PRQWKV. :LOGW\SH. “ Q 

(211) . “ Q 

(212) . “ Q 

(213) . 7J7J. “ Q 

(214) . “ Q 

(215) . “ Q 

(216) . GLIIHUHQFH. . . . SYDOXH. (. (. (. :LOGW\SH. “ Q 

(217) . “ Q 

(218) . “ Q 

(219) . 7J7J. “ Q 

(220) . “ Q 

(221) . “ Q 

(222) . GLIIHUHQFH. . . . SYDOXH. . (. . ƃ  . 7J7J. $JH. 7DVK7. . r ee rP Fo 7DVK7. . 6XSSOHPHQWDO7DEOH/LVWRISULPDU\DQGVHFRQGDU\DQWLERGLHVXVHGLQWKLVVWXG\ $QWLERG\. 'LOXWLRQ. $QWL+X&'. . +RVW VSHFLHV 0RXVH. $QWL&DOUHWLQLQ. . *RDW. $QWLQ1RV. . 5DEELW. $QWL6R[. . *RDW. $QWL&NLW. . *RDW. $QWLȕ,,,7XEXOLQ. . $QWL0RXVH$OH[D)OXRU. ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 26 of 42. 55,'QXPEHU $%B. 6RXUFH. 0ROHFXODU3UREHV$. $%B 6ZDQW&* $%B. 0LOOLSRUH$%. $%B. 6DQWD&UX]%LRWHFKQRORJ\VF. $%B. &HGHUODQH &DQDGD

(223) $). 0RXVH. $%B. $EFDPDE. . 'RQNH\. $%B. -DFNVRQ,PPXQR5HVHDUFK. $QWL5DEELW$OH[D)OXRU. . 'RQNH\. $%B. -DFNVRQ,PPXQR5HVHDUFK. $QWL*RDW$OH[D)ORXU. . %RYLQH. $%B. -DFNVRQ,PPXQR5HVHDUFK.   .

(224) Page 27 of 42.  . r ee rP Fo ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Neurogastroenterology and Motility.  )LJ [PP ['3,

(225) .  .

(226) Neurogastroenterology and Motility.  . r ee rP Fo ew vi Re. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60. Page 28 of 42.  )LJ [PP ['3,

(227) .  .

Références

Documents relatifs

MPI’s remote memory access interface defines one-sided communication operations, data consistency, and synchronization models for accessing memory regions that are exposed through

)OH[LELOLW\RISURFHVVHVKDVEHHQLQYHVWLJDWHGLQ WKHFRQWH[WRIFHQWUDOL]HGSURFHVVHV:HGLVWLQJXLVK EHWZHHQWZRGLIIHUHQWDSSURDFKHVWKHYDULDQWEDVHG DSSURDFK DQG

We make the hypothesis that the shortest Wikipedia path query that maximally containment Q(W) is the best navigational path to represent in Wikipedia the predicate.. p of the

scientifique et politique du phénomène, l’instinct le cède au conditionnement qui opère par les stimuli du contexte (ici l’angoisse collective produite par la

We remark nevertheless, from qualitative analyses of use of the regulator in real driving conditions, and from the lived experience of this use by subjects, that this drop in trust in

$IWHUVHYHUDOIHUPHQWDWLRQVWKHORVVHVRIPDVVEHWZHHQWKH EHJLQQLQJDQGWKHHQGRIWKHIHUPHQWDWLRQHYROYHLQWKHVDPH SURSRUWLRQV LQGHSHQGHQWO\ RI WKH TXDQWLW\ XVHG

,Q WKH ILUVW SDUW RI WKH WKHVLV ZH GHPRQVWUDWH WKH H[LVWHQFH RI WKUHH UHJLPHV RI WKH 153 GLVFKDUJH LQ DLU DW DWPRVSKHULF SUHVVXUH DQG DW D IL[HG WHPSHUDWXUH RI. DQG WKHQ ZH

Despite this, trade shows are incredibly relevant in highlighting organizational and inter- organizational dynamics: they gather the main actors of an industry or a