JVI Accepted Manuscript Posted Online 6 May 2015 J. Virol. doi:10.1128/JVI.00603-15 Copyright © 2015, American Society for Microbiology. All Rights Reserved.
1
7KHKXPDQF\WRPHJDORYLUXVS8/PRGXODWHVWHJXPHQWDWLRQDQGFDSVLG
2
DFFXPXODWLRQDWWKHYLUDODVVHPEO\FRPSOH[
3
4
5XQQLQJWLWOH5ROHRIS8/LQ+&09PRUSKRJHQHVLV
5
6
,ODULD&DSSDGRQD&ODULVVD9LOOLQJHU*DEL6FKXW]LXV7KRPDV0HUWHQVDQG-HQVYRQ(LQHP
7 8
,QVWLWXWHRI9LURORJ\8QLYHUVLW\0HGLFDO&HQWHU8OP8OP*HUPDQ\
9
(OHFWURQ0LFURVFRS\)DFLOLW\8OP8QLYHUVLW\8OP*HUPDQ\
10
11
12
13
14
15
16
17
&RUUHVSRQGHQFHWR
18
-HQVYRQ(LQHP
19
,QVWLWXWHRI9LURORJ\
20
8QLYHUVLW\0HGLFDO&HQWHU8OP
21
8OP
22
*HUPDQ\
23
3KRQH
24
)D[
25
(PDLOMHQVYRQHLQHP#XQLNOLQLNXOPGH
26
1
27
$EVWUDFW
28
+XPDQ F\WRPHJDORYLUXV +&09 WHJXPHQW SURWHLQ S8/ LV DQ LQWHUDFWLRQ SDUWQHU RI
29
S8/DQGKLJKO\FRQVHUYHGDPRQJKHUSHVYLUXVHV,WLVFORVHO\DVVRFLDWHGZLWKWKHFDSVLGDQG
30
KDV DQ LPSRUWDQW IXQFWLRQ HDUO\ LQ LQIHFWLRQ +HUH ZH UHSRUW D VSHFLILF UROH RI S8/ LQ
31
WHJXPHQWDWLRQRIFDSVLGVLQWKH F\WRSODVP$QHZO\JHQHUDWHG PXWDQW YLUXV7%VWRS LQ
32
ZKLFK H[SUHVVLRQ RI S8/ LV EORFNHG H[KLELWHG D VHYHUH LPSDLUPHQW LQ FHOOWRFHOO VSUHDG
33
DQG UHOHDVH RI LQIHFWLYLW\ IURP LQIHFWHG FHOOV 8OWUDVWUXFWXUDO DQDO\VLV RI 7%VWRS LQIHFWHG
34
FHOOV FOHDUO\ VKRZHG F\WRSODVPLF DFFXPXODWLRQV RI QRQHQYHORSHG FDSVLGV WKDW ZHUH RQO\
35
SDUWLDOO\ WHJXPHQWHG LQGLFDWLQJ WKDW WKHVH FDSVLGV IDLOHG WR FRPSOHWH WHJXPHQWDWLRQ
36
1HYHUWKHOHVV WKHVH DFFXPXODWLRQV ZHUH SRVLWLYH IRU +&09 LQQHU WHJXPHQW SURWHLQV SS
37
DQG S8/ VXJJHVWLQJ WKDW WKHLU DWWDFKPHQW WR FDSVLGV RFFXUV LQGHSHQGHQWO\ RI S8/
38
'HVSLWH WKHVH PRUSKRORJLFDO DOWHUDWLRQV IXOO\ HQYHORSHG YLUXV SDUWLFOHV ZHUH IRXQG LQ WKH
39
H[WUDFHOOXODU VSDFH DQG DW WKH YLUDO DVVHPEO\ FRPSOH[ Y$& RI 7%VWRS LQIHFWHG FHOOV
40
LQGLFDWLQJ WKDW S8/ LV QRW HVVHQWLDO IRU WKH JHQHUDWLRQ RI YLULRQV :H FRQILUPHG ILQGLQJV
41
WKDW LQFRUSRUDWLRQ RI S8/ LQWR YLULRQV LV LPSDLUHG LQ DEVHQFH RI S8/ ,QWHUHVWLQJO\
42
S8/H[KLELWHGDVWURQJQXFOHDUORFDOL]DWLRQLQWUDQVIHFWHGFHOOVZKHUHDVLWZDVH[FOXVLYHO\
43
IRXQG DW WKH Y$& LQ WKH FRQWH[W RI YLUXV LQIHFWLRQ &RORFDOL]DWLRQ RI S8/ DQG S8/DW
44
WKH Y$& LV FRQVLVWHQW ZLWK WKHLU LQWHUDFWLRQ :H DOVR IRXQG D VKLIW WR D PRUH QXFOHDU
45
ORFDOL]DWLRQRIS8/ZKHQWKHH[SUHVVLRQRIS8/ZDVUHGXFHG6XPPDUL]LQJRXUUHVXOWV
46
ZH K\SRWKHVL]H WKDW S8/ GLUHFWV S8/ WR WKH Y$& WR SURPRWH WHJXPHQWDWLRQ DQG
47
VHFRQGDU\HQYHORSPHQWRIFDSVLGV
48
,PSRUWDQFH
49
*HQHUDWLRQ RI LQIHFWLRXV +&09 SDUWLFOHV UHTXLUHV DQ RUJDQL]HG DQG PXOWLVWHS SURFHVV
50
LQYROYLQJ WKH DFWLRQ RI VHYHUDO YLUDO DQG FHOOXODU SURWHLQV DV ZHOO DV SURWHLQSURWHLQ
51
LQWHUDFWLRQV $ EHWWHU XQGHUVWDQGLQJ RI WKHVH SURFHVVHV LV LPSRUWDQW IRU XQGHUVWDQGLQJ WKH
52
ELRORJ\ RI +&09 DQG PD\ KHOS WR LGHQWLI\ WDUJHWV IRU DQWLYLUDO LQWHUYHQWLRQ +HUH ZH 2
53
LGHQWLILHG WHJXPHQW SURWHLQ S8/ WR IXQFWLRQ LQ WHJXPHQWDWLRQ DQG SURSHU WUDIILFNLQJ RI
54
FDSVLGV GXULQJ ODWH SKDVHV RI LQIHFWLRQ $OWKRXJK S8/ LV QRW HVVHQWLDO IRU JHQHUDWLRQ DQG
55
UHOHDVHRILQIHFWLRXVYLULRQVLWVDEVHQFHOHGWRPDVVLYHDFFXPXODWLRQVRISDUWLDOO\WHJXPHQWHG
56
FDSVLGV DW WKH FHOO SHULSKHU\ 'HWHFWLRQ RI S8/ DW WKHVH DFFXPXODWLRQV LQGLFDWHG IRU D
57
S8/ LQGHSHQGHQW DWWDFKPHQW RI S8/ WR WKH FDSVLG 2Q WKH RWKHU KDQG ORFDOL]DWLRQ RI
58
S8/ WR WKH Y$& GXULQJ LQIHFWLRQ DSSHDUHG WR EH GHSHQGHQW RQ WHJXPHQW SURWHLQ S8/
59
ZKLFK VXJJHVWV DQ LQWULFDWH LQWHUSOD\ RI WKHVH SURWHLQV IRU QRUPDO JHQHUDWLRQ RI LQIHFWLRXV
60
YLUXVSURJHQ\
61
,QWURGXFWLRQ
62
9LULRQV RI KXPDQ F\WRPHJDORYLUXV +&09 FRQVLVW RI WKH IRXU PDMRU FRPSRQHQWV WKDW DUH
63
FKDUDFWHULVWLFIRUKHUSHVYLUXVSDUWLFOHVWKHGV'1$JHQRPHWKDWLVSDFNDJHGLQDQLFRVDKHGUDO
64
FDSVLG WKH WHJXPHQW DQG WKH YLUDO HQYHORSH 7KH WHJXPHQW LV D OD\HU RI YLUDO DQG FHOOXODU
65
SURWHLQVWKDWKDVDFULWLFDOUROHIRUWKHJHQHUDWLRQRIYLULRQVE\FRQQHFWLQJWKHHQYHORSHZLWK
66
WKHFDSVLG,WLVDYHU\FRPSOH[VWUXFWXUHWKDWLQWKHFDVHRI+&09FRQVLVWVRIPRUHWKDQ
67
GLIIHUHQW YLUDO SURWHLQV D QXPEHU RI FHOOXODU SURWHLQV DQG P51$¶V +&09 FDSVLGV
68
DFTXLUHPRVWRIWKHLUWHJXPHQWDQGWKHLUHQYHORSHDWWKHF\WRSODVPLFYLUDODVVHPEO\FRPSOH[
69
Y$& 7KHY$&LVFKDUDFWHULVWLFIRU+&09LQIHFWHGFHOOVDQGWKHUHVXOWRIDYLUDOO\LQGXFHG
70
UHRUJDQL]DWLRQ RI *ROJL DQG HQGRVRPDO PHPEUDQHV 0DQ\ WHJXPHQW SURWHLQV KDYH
71
EHHQ IRXQG WR DFFXPXODWH DW WKH Y$& GXULQJ LQIHFWLRQ ZKLFK HPSKDVL]HV WKHLU
72
UROH IRU YLULRQ DVVHPEO\ ,Q DGGLWLRQ WR WKHLU IXQFWLRQ DV VWUXFWXUDO YLULRQ FRPSRQHQWV
73
WHJXPHQWSURWHLQVDFWDWVHYHUDOVWHSVRIWKHYLUDOLQIHFWLRQF\FOH7KHVHLQFOXGHLQLWLDWLRQDQG
74
UHJXODWLRQ RI YLUDO UHSOLFDWLRQ UHOHDVH RI YLUDO '1$ LQWR WKH QXFOHXV LPPXQH HYDVLRQ
75
LQWUDFHOOXODU WUDIILFNLQJ RI YLUXV SDUWLFOHV DQG DVVHPEO\ RI LQIHFWLRXV SURJHQ\
76
)RUPDWLRQ RI WKH WHJXPHQW GXULQJ YLULRQ DVVHPEO\ LV D SRRUO\ XQGHUVWRRG SURFHVV 7KHUH LV
77
LQFUHDVLQJ HYLGHQFH RI DQ XQGHUO\LQJ LQWULFDWH QHWZRUN RI SURWHLQSURWHLQ LQWHUDFWLRQV WKDW
78
UHJXODWHVWHJXPHQWIRUPDWLRQZKLFKVWDUWVZLWKWKHDWWDFKPHQWRIYLUDOSURWHLQVWRWKHFDSVLG 3
79
7KH WHJXPHQW LV GLYLGHG LQWR D FDSVLGSUR[LPDO RU LQQHU DQG D FDSVLGGLVWDO RU RXWHU
80
WHJXPHQW OD\HU +&09 WHJXPHQW SURWHLQV RI WKH LQQHU WHJXPHQW DUH WLJKWO\ DVVRFLDWHG ZLWK
81
WKHFDSVLGDQGWKHUHIRUHOLNHO\FDQGLGDWHVWRUHJXODWHILUVWVWHSVRIWHJXPHQWDWLRQ 7KHVH
82
SURWHLQVLQFOXGHWKH+&09SURWHLQVSSS8/DQGS8/:KHUHDVSSLVDQ+&09
83
VSHFLILF WHJXPHQW SURWHLQ IRU S8/ NQRZQ DV WKH ODUJH WHJXPHQW SURWHLQ DQG S8/
84
KRPRORJRXV SURWHLQV KDYH EHHQ LGHQWLILHG LQ DOO KHUSHVYLUXV VXEIDPLOLHV 7KH UL32
85
HQFRGHG SS KDV EHHQ VKRZQ WR IXQFWLRQ LQ VWDELOL]LQJ FDSVLGV DQG LQ WKHLU LQWUDFHOOXODU
86
WUDIILFNLQJ :KLOHS8/LVHVVHQWLDOIRUYLUDOUHSOLFDWLRQS8/EHORQJVWR
87
WKHFODVVRI+&09SURWHLQVWKDWDXJPHQWVYLUDOJURZWK $PXWDQWYLUXVZLWKDODUJH
88
VXEVWLWXWLRQRIWKHUL47RSHQUHDGLQJIUDPH25) KDVEHHQVKRZQWRDFFXPXODWHIROG
89
UHGXFHG H[WUDFHOOXODU YLUXV WLWHUV S8/ ZLWK D PROHFXODU ZHLJKW RI N'D LV D
90
FRPSRQHQWRIWKHLQQHUWHJXPHQWRIPDWXUHYLULRQVEXWLVDOVRIRXQGLQGHQVHERGLHV'% DQG
91
QRQLQIHFWLRXV HQYHORSHG SDUWLFOHV 1,(36 ,W LV SDUW RI D ODUJHU SURWHLQ FRPSOH[ LQ
92
LQIHFWLRQ FRQVLVWLQJ RI DW OHDVW S8/ S8/ S8/ DQG WKH UL86HQFRGHG PDMRU FDSVLG
93
SURWHLQ 0&3 S8/ LV VHOILQWHUDFWLQJ WR IRUP ROLJRPHUV DQG LV DOVR GLUHFWO\
94
LQWHUDFWLQJZLWKWKHODUJHWHJXPHQWSURWHLQS8/ ,QFRUSRUDWLRQRIS8/LQWRYLULRQV
95
LVLPSDLUHGLQWKHDEVHQFHRIS8/ZKLFKUHVXOWVLQYLULRQVGHIHFWLYHIRUERWKS8/DQG
96
S8/7KHVHYLULRQVH[KLELWDGHIHFWDIWHUYLUXVHQWU\SULRUWRLPPHGLDWHHDUO\WUDQVFULSWLRQ
97
ZKLFKPD\RFFXUDWWKHOHYHORIJHQRPHUHOHDVHLQWRWKHQXFOHXV
98
7KH KRPRORJV RI S8/ DQG S8/ LQ WKH DOSKDKHUSHVYLUXVHV +HUSHV 6LPSOH[ 9LUXV
99
+69 DQG 3VHXGRUDELHVYLUXV 3U9 DUH HQFRGHG E\ WKH UL37 DQG UL36 25)V DQG DUH
100
NQRZQ DV S8/ DQG S8/ 6HYHUDO IXQFWLRQV KDYH EHHQ DVFULEHG WR S8/ GXULQJ HDUO\
101
DQG ODWH SKDVHV RI LQIHFWLRQ 8SRQ HQWU\ S8/ UHPDLQV DVVRFLDWHG ZLWK LQWUD
102
F\WRSODVPLFFDSVLGVWRIDFLOLWDWHWRJHWKHUZLWKS8/WKHLUWUDQVSRUWDORQJPLFURWXEXOHVWRWKH
103
QXFOHXV $OWKRXJKS8/LVQRWUHTXLUHGLWVSUHVHQFHDFFHOHUDWHVFDSVLGWUDQVSRUWWR
104
WKHQXFOHXV ,QDGGLWLRQS8/LVDOVRLQYROYHGLQPRGXODWLQJFHOOXODUUHVSRQVHVE\ 4
105
WULJJHULQJ 1)κ% DFWLYDWLRQ WKURXJK 71) UHFHSWRU±DVVRFLDWHG IDFWRU 'XULQJ WKH ODWH
106
SKDVHRILQIHFWLRQS8/UHJXODWHVYLULRQPDWXUDWLRQFDSVLGWUDIILFNLQJDQGHJUHVV
107
,QLQIHFWLRQVZLWKPXWDQWYLUXVHVODFNLQJS8/QRQHQYHORSHGFDSVLGVDFFXPXODWH
108
LQWKHF\WRSODVPDVDUHVXOWIURPHLWKHUDFRPSOHWHEORFNRIVHFRQGDU\HQYHORSPHQWDVVHHQLQ
109
+69 RU D GUDVWLF EXW QRW OHWKDO GHIHFW ZLWK RQO\ OLWWOH HQYHORSPHQW DV REVHUYHG LQ 3U9
110
&RQVHTXHQWO\HJUHVVRILQIHFWLRXVYLULRQVKLJKO\GHSHQGVRQS8/+69DQG3U9
111
$WWDFKPHQW RI S8/ RQ FDSVLGV LV UHTXLUHG IRU GLUHFWLQJ WKHP WR WKH trans*ROJL
112
QHWZRUN7*1 ZKHUHVHFRQGDU\HQYHORSPHQWRFFXUV&DSVLGVDUHWDUJHWHGWRWKH7*1E\DQ
113
LQWHUDFWLRQRIS8/ZLWKFHOOXODUSURWHLQ3%$* %LQGLQJRIS8/WRFDSVLGVLV
114
UHJXODWHG E\ WKH ODUJH WHJXPHQW SURWHLQ S8/ DQG UHTXLUHV WKHLU LQWHUDFWLRQ
115
$WWDFKPHQWRIS8/VHHPVWRVWDUWDOUHDG\LQWKHQXFOHXV 7KHLQWHUDFWLRQRIS8/
116
DQGS8/LVKLJKO\FRQVHUYHGLQDOSKDKHUSHVYLUXVHVDQGDQHVVHQWLDOUHTXLUHPHQWIRUYLULRQ
117
PRUSKRJHQHVLV )XQFWLRQVRIWKHLQGLYLGXDOFRPSOH[SDUWQHUVDUHVWURQJO\LQWHUWZLQHG
118
ZLWK WKHLU FRPSOH[ IRUPDWLRQ 7KH ORFDOL]DWLRQ RI S8/ DW WKH 7*1 LV LQGHSHQGHQW RI
119
FDSVLGV DQG UHTXLUHV WKH SUHVHQFH S8/ ,Q WXUQ WKH LQWHUDFWLRQ ZLWK S8/
120
VWDELOL]HVS8/
121
7KH H[DFW UROH RI +&09 S8/ GXULQJ WKH ODWH SKDVH RI LQIHFWLRQ LV QRW FOHDU ZKLFK LV
122
VXUSULVLQJLQWKHOLJKWRIWKHVWURQJFRQVHUYDWLRQRIWKLVSURWHLQDQGLWVLPSRUWDQFHIRUYLULRQ
123
PRUSKRJHQHVLVLQRWKHUKHUSHVYLUXVHV7RJDLQLQVLJKWLQWRWKHUROHRI+&09S8/GXULQJ
124
WKHODWHSKDVHRILQIHFWLRQZHJHQHUDWHGDPXWDQWYLUXV7%VWRSWKDWLVXQDEOHWRH[SUHVV
125
S8/ 7KLV PXWDQW YLUXV ZDV XVHG WR HYDOXDWH YLUDO JURZWK LQ DEVHQFH RI S8/ DQG WR
126
GHWHUPLQH LWV UROH LQ WHJXPHQWDWLRQ DQG VHFRQGDU\ HQYHORSPHQW RI +&09 E\ HOHFWURQ
127
PLFURVFRS\DIWHUKLJKSUHVVXUHIUHH]LQJDQGIUHH]HVXEVWLWXWLRQ*URZWKSURSHUWLHVRIRXU7%
128
VWRS YLUXV ZHUH VLPLODU WR WKRVH RI D SUHYLRXV UL47PXWDQW ZLWK WKH DGGLWLRQ RI D
129
VHYHUH GHIHFW LQ FHOOWRFHOO VSUHDG DQG DQ LPSDLUHG HJUHVV RIYLUXV SDUWLFOHV 8OWUDVWUXFWXUDO
130
H[DPLQDWLRQ RI YLUDO PRUSKRJHQHVLV DQG LPPXQRIOXRUHVFHQFH UHYHDOHG WKDW S8/ LV 5
131
LQYROYHGLQWKHSURFHVVHVRIWHJXPHQWDWLRQSURSHUFDSVLGVWUDIILFNLQJDQGWKHLUWUDSSLQJDWWKH
132
Y$&UHVXOWLQJLQWKHDFFXPXODWLRQRISDUWLDOO\WHJXPHQWHGDQGQRQHQYHORSHGFDSVLGVLQWKH
133
F\WRSODVP ZKHQ S8/ LV PLVVLQJ )XUWKHUPRUH JHQHUDWLRQ RI PXWDQW YLUXVHV ZLWK )ODJ
134
WDJJHG S8/ HQDEOHG WKH GHWHFWLRQ RI S8/ LQ LPPXQRIOXRUHVFHQFH DQDO\VLV 7KH
135
ORFDOL]DWLRQRIS8/DWWKHY$&ZDVLQGHSHQGHQWRIWKHSUHVHQFHFDSVLGVDQGZDVUHJXODWHG
136
E\S8/&ROOHFWLYHO\WKHVHUHVXOWVRIIHUQHZLQVLJKWVLQWRWKHIXQFWLRQRIS8/GXULQJWKH
137
ODWH SKDVH RI +&09 LQIHFWLRQ DQG LQWR WKH UHJXODWLRQ RI WKH LQWUDFHOOXODU ORFDOL]DWLRQ RI
138
S8/:HSURSRVHDPHFKDQLVPE\ZKLFKORFDOL]DWLRQRIS8/DWWKHY$&LVUHJXODWHGE\
139
LWVFRPSOH[SDUWQHUS8/DQGSURPRWHVWHJXPHQWDWLRQVHFRQGDU\HQYHORSPHQWDQGFRUUHFW
140
WUDIILFNLQJRIFDSVLGVWRJHQHUDWHPDWXUHLQIHFWLRXVYLUXVSURJHQ\
141
0DWHULDOVDQG0HWKRGV
142
&HOOV +XPDQ IRUHVNLQ ILEUREODVWV +))V DQG KXPDQ HPEU\RQLF OXQJ ILEUREODVWV 05&
143
(XURSHDQ&ROOHFWLRQRI&HOO&XOWXUHV ZHUHPDLQWDLQHGLQPLQLPDOHVVHQWLDOPHGLXP0(0
144
*LEFR%5/ VXSSOHPHQWHG ZLWK IHWDO FDOI VHUXP )&6 *LEFR%5/ DQG QRQ
145
HVVHQWLDODPLQRDFLGV%LRFKURP$* +))VZHUHXVHGXQWLOSDVVDJHIRULQIHFWLRQVWXGLHV
146
05& FHOOV ZHUH XVHG EHWZHHQ SDVVDJH DQG IRU WKH UHFRQVWLWXWLRQ RI YLUXV PXWDQWV
147
+XPDQ HSLWKHOLDO FDUFLQRPD FHOOV +H/D ZHUH PDLQWDLQHG LQ 'XOEHFFR¶V PRGLILHG (DJOH
148
PHGLXP '0(0 *LEFR%5/ VXSSOHPHQWHG ZLWK )&6 DQG QRQHVVHQWLDO DPLQR
149
DFLGV +H/D FHOOV ZHUH XVHG LQ WUDQVIHFWLRQ H[SHULPHQWV DQG LQGLUHFW LPPXQRIOXRUHVFHQFH
150
DQDO\VHV $OO PHGLD ZHUH DGGLWLRQDOO\ VXSSOHPHQWHG ZLWK SHQLFLOOLQVWUHSWRP\FLQ
151
IROG3$$/DERUDWRULHV DQG/JOXWDPLQHP03$$/DERUDWRULHV
152
%$&PXWDJHQHVLVDQGYLUXVUHFRQVWLWXWLRQ5HFRPELQDQWEDFWHULDO DUWLILFLDO FKURPRVRPHV
153
%$&V ZHUHJHQHUDWHGXVLQJDPDUNHUOHVVWZRVWHS5('*$0UHFRPELQDWLRQSURWRFRO
154
5('UHFRPELQDWLRQZDVXVHGWRPRGLI\WKH7%%$&%$&WKDWLVGHULYHGIURPWKH
155
HQGRWKHOLRWURSLF+&09VWUDLQ7%(
6
156
7KH %$& RI PXWDQW YLUXV 7%VWRS ZDV JHQHUDWHG ZLWK SULPHUV HS8/VWRSIRU
157
***7&*&*&**&&*777**&&$&&*&*&*&*&*7&&$7*WDJ&$$**&*&$&**7$
158
*$77$**$7*$&*$&*$7$$*7$***
159
&7*&7&7$7&$$&77777*$$$7&7$&&*7*&*&&77*FWD&$7**$&*&*&*&*&*
160
*7*&$$&&$$77$$&&$$77&7*$77$* )RU WKH %$& RI WKH UHYHUWDQW YLUXV 7%
161
UHY WKH VWRS FRGRQ DQG WKH IUDPH VKLIW LQ WKH 7%VWRS %$& ZHUH UHSDLUHG E\ 5('
162
UHFRPELQDWLRQ
163
***7&*&*&**&&*777**&&$&&*&*&*&*&*7&&$7*DWJJFW$**&*&$&**7$
164
*$77$**$7*$&*$&*$7$$*7$***
165
&7*&7&7$7&$$&77777*$$$7&7$&&*7*&*&&7DJFFDW&$7**$&*&*&*&*&*
166
*7*&$$&&$$77$$&&$$77&7*$77$* )RU LQVHUWLRQV RI WKH IODJWDJ VHTXHQFH LQWR
167
WKH
168
*7&*&*&**&&*777**&&$&&*&*&*&*&*7&&$7*$7*JDWWDFDDJJDFJDWJDWJDFDDJ
169
*&$$**&*$**$7*$&*$&*$7$$*7$***
170
*&7*&7&7$7&$$&77777*$$$7&7$&&*7*&*&&77*&FWWJWFDWFDWFJWFFWWJWDDWF&$
171
7&$7**&$$&&$$77$$&&$$77&7*$77$* IRU WKH PXWDQW YLUXV 7%1IODJ DQG
172
SULPHUV
173
*&&&*&&**&7&*$&$7&**7*7&&&7*&&*&&**&&7&*JDWWDFDDJJDFJDWJDWJDFDDJ
174
&&$7*$$$$**$7*$&*$&*$7$$*7$***
175
$7*7&*&&&7**7**&$*&7**&&7*&*7*$&777&$7**FWWJWFDWFDWFJWFFWWJWDDWF&*
176
$**&&*&$$&&$$77$$&&$$77&7*$77$* WR JHQHUDWH WKH 7%&IODJ YLUXV
177
3ULPHUV FRQWDLQHG VHTXHQFHV RI KRPRORJ\ XSVWUHDP DQG GRZQVWUHDP RI WKH VLWHV WR EH
178
PXWDWHG WKH PXWDWLRQ VPDOO OHWWHUV DQG KRPRORJ\ WR WKH S(3NDQ6 WHPSODWH SODVPLG
179
XQGHUOLQHG $OO JHQHUDWHG UHFRPELQDQW %$& '1$V ZHUH FRQWUROOHG IRU LQWHJULW\ DQG
180
FRUUHFWQHVVE\UHVWULFWLRQOHQJWKSRO\PRUSKLVPDQGVHTXHQFLQJRIWKHPXWDWHGUHJLRQ
7%%$&
ZLWK
ZH
DQG
HS8/VWRSUHY
SULPHUV
HS8/UHVFIRU
DQG
XVHG
HS8/UHVFUHY
SULPHUV
HS1IODJIRU
HS1IODJUHY
HS&IODJIRU
7
DQG
HS&IODJUHY
181
05& FHOOV ZHUH XVHG IRU WKH UHFRQVWLWXWLRQV RI UHFRPELQDQW YLUXVHV DQG YLUXV VWRFN
182
SURGXFWLRQ 7KH UHFRQVWLWXWLRQ IURP %$& '1$ ZDV SHUIRUPHG H[DFWO\ DV SUHYLRXVO\
183
GHVFULEHG 5HFRQVWLWXWLRQ RI WKH 7%VWRS YLUXV IURP 7%VWRS %$& '1$ ZDV
184
SRVVLEOHEXWUHTXLUHGDQH[WHQGHGSHULRGRI FXOWLYDWLRQXQWLOFHOOVZHUHFRPSOHWHO\LQIHFWHG
185
DQG UHVXOWLQJ YLUXV VWRFNV H[KLELWHG YLUXV \LHOGV ORZHU WKDQ LQIHFWLRXV SDUWLFOHV SHU PO
186
S8/H[SUHVVLQJ 05& FHOOV GHVLJQDWHG W05& ZHUH JHQHUDWHG E\ OHQWLYLUDO
187
WUDQVGXFWLRQWRJHQHUDWHYLUXVVWRFNVRI7%VWRSYLUXVZLWKKLJKHUWLWHUV(OHFWURSRUDWLRQRI
188
WKHVH FHOOV ZLWK 7%VWRS %$& '1$ DQG VXEVHTXHQW SURSDJDWLRQ RI 7%VWRS YLUXV
189
UHVXOWHGLQSKHQRW\SLFDOO\FRPSOHPHQWHGYLUXV7%VWRS8/
190
*HQHUDWLRQ RI W05& OHQWLYLUXVWUDQVGXFHG 05&H[SUHVVLQJS8/$ OHQWLYLUXV
191
H[SUHVVLQJ D &WHUPLQDOO\ 0\FWDJJHG S8/ ZDV JHQHUDWHG E\ XVLQJ WKH *DWHZD\ FORQLQJ
192
V\VWHP,QYLWURJHQ DQGWKHOHQWLYLUDOYHFWRUS/HQWL9'(67,QYLWURJHQ 7KHVHTXHQFH
193
RIWKH P\FWDJZDVDGGHGWRWKH8/VHTXHQFHE\SRO\PHUDVH FKDLQUHDFWLRQ3&5 XVLQJ
194
SULPHUV
195
DFJDDWWFWFDFDJDWFWWFWWFDJDDDWDDJWWWWWJWWFWJJFJDJJFFJJFJJDQGFORQHGLQWRWKH*DWHZD\YHFWRU
196
S(175$,QYLWURJHQ E\XVLQJBamH,DQGEcoR,UHVWULFWLRQVLWHV7KH8/P\FVHTXHQFH
197
ZDV WUDQVIHUUHG IURP WKH S(175$ YHFWRU LQWR WKH S/HQWL9'(67 YHFWRU E\ WKH /5
198
UHDFWLRQDFFRUGLQJWRWKHPDQXIDFWXUHVSURWRFROUHVXOWLQJLQS/HQWL8/P\F3XULILHG'1$
199
RI S/HQWL8/P\F ZDV XVHG WR JHQHUDWH OHQWLYLUXV VWRFN ZLWK WKH 9LUD3RZHU /HQWLYLUDO
200
([SUHVVLRQ 6\VWHP ,QYLWURJHQ 7KLV OHQWLYLUXV ZDV XVHG IRU WUDQVGXFWLRQ RI 05& LQ
201
SUHVHQFH RI JPO SRO\EUHQH 6LJPD /HQWLYLUDO WUDQVGXFHG FHOOV ZHUH VHOHFWHG E\ D
202
VXEVHTXHQWLQFXEDWLRQZLWKJPO%ODVWLFLGLQH,QYLWURJHQ IRUDWOHDVWILYHGD\VDQGWKHLU
203
VXEVHTXHQWFXOWLYDWLRQZLWKJPO%ODVWLFLGLQIRUIXUWKHUH[SDQVLRQ$OLTXRWVRIW05&
204
FHOOVZHUHVWRUHGLQOLTXLGQLWURJHQDQGIUHVKO\WKDZHGIRUUHFRQVWLWXWLRQDQGSURSDJDWLRQRI
205
7%VWRSYLUXV
H[IRU
WFJJDWFFDWJDWJJFDDJJFJFDFJJ
8
DQG
H[P\FUHY
206
$QWLERGLHV+&09HQFRGHGDQGFHOOXODUSURWHLQVZHUHGHWHFWHGZLWKPRQRFORQDODQWLERGLHV
207
0$EV LQ IRFXV H[SDQVLRQ DVVD\V WLWUDWLRQ :HVWHUQ EORW DQDO\VHV DQG LQGLUHFW
208
LPPXQRIOXRUHVFHQFH VWXGLHV 7KH 0$EV XVHG LQ WKH SUHVHQW VWXG\ LQFOXGHG WKRVH GLUHFWHG
209
DJDLQVWSSFORQH&6DQWD&UX]%LRWHFK SS0$E SS8/;S
210
0&30$E ,(0$E $FWLQ6LJPD$OGULFK DQG)ODJ06LJPD$OGULFK
211
+&09 WHJXPHQW SURWHLQV S8/ DQG S8/ ZHUH GHWHFWHG ZLWK SUHYLRXVO\ GHVFULEHG
212
SRO\FORQDO DQWLERGLHV 7KH DQWLSS SRO\FORQDO DQWLERG\ ZDV UHFHLYHG IURP 7K
213
6WDPPLQJHU8QLYHUVLW\RI(UODQJHQ 7KH8/VSHFLILFSRO\FORQDOVHUDXVHGLQ:HVWHUQ
214
EORWDQDO\VHVZDVJHQHUDWHGLQUDEELWVLQMHFWHGZLWKDS8/&WHUPLQDOIUDJPHQWFRPSULVLQJ
215
DPLQRDFLGUHVLGXHVWRRIWKH+&09VWUDLQ7%%$&)RUWKHDQWLERG\JHQHUDWLRQ
216
ZH IROORZHG WKH VDPH VWUDWHJ\ DV SUHYLRXVO\ GHVFULEHG IRU WKDW RI D SRO\FORQDO DQWLERG\
217
DJDLQVW S8/ *RDW DQWLPRXVH DQG JRDW DQWLUDEELW VHFRQGDU\ DQWLERGLHV FRQMXJDWHG
218
ZLWK $OH[D)OXRU RU ,QYLWURJHQ ZHUH XVHG IRU IRFXV H[SDQVLRQ DVVD\ DQG
219
LPPXQRIOXRUHVFHQFH VWXGLHV JRDW DQWLPRXVH RU JRDW DQWLUDEELW VHFRQGDU\ DQWLERGLHV
220
FRQMXJDWHG ZLWK KRUVHUDGLVK SHUR[LGDVH +53 3LHUFH ZHUH XVHGIRU :HVWHUQ EORW DQDO\VHV
221
DQGDQ+53FRQMXJDWHGUDEELWDQWLPRXVHDQWLERG\'$.2 ZDVXVHGIRUWLWUDWLRQ
222
,QGLUHFWLPPXQRIOXRUHVFHQFH)RULQGLUHFWLPPXQRIOXRUHVFHQFHVWXGLHVRI+&09LQIHFWHG
223
FHOOV+))VZHUHVHHGHGLQ6OLGHHLJKWZHOOSODWHV,ELGL*PE+ DQGV\QFKURQL]HGIRUK
224
E\VHUXPVWDUYDWLRQ&HOOVZHUHWKHQLQIHFWHGZLWKDPXOWLSOLFLW\RILQIHFWLRQ02, EHWZHHQ
225
$WWKHUHTXLUHGWLPHSRVWLQIHFWLRQFHOOVZHUHZDVKHGWZLFHZLWK3%6DQGIL[HGZLWK
226
3)$ LQ 3%6 IRU PLQ DW & DQG VWDLQHG DV GHVFULEHG SUHYLRXVO\ ,ELGL VOLGHV
227
DOORZHGGLUHFWLPDJLQJZLWKRXWSULRUPRXQWLQJXVLQJWKHLQYHUWHGIOXRUHVFHQFHPLFURVFRSH,I
228
QRW VWDWHG RWKHUZLVH FRQIRFDO LPDJHV ZHUH WDNHQ ZLWK D [ REMHFWLYH OHQV RI DQ $[LR
229
2EVHUYHU=IOXRUHVFHQFHPLFURVFRSHHTXLSSHGZLWKDQ$SRWRPH=HLVV DQGWKH$[LRYLVLRQ
230
VRIWZDUH
9
231
)RU WKH LQGLUHFW LPPXQRIOXRUHVFHQFH RI WUDQVIHFWHG FHOOV +H/D FHOOV ZHUH JURZQ RQ JODVV
232
FRYHUVOLSVLQZHOOSODWHVDQGWUDQVIHFWHGXVLQJ/LSRIHFWDPLQ/7;DQGIL[HGZLWK3)$
233
DIWHUKDVGHVFULEHGSUHYLRXVO\
234
*URZWK DQDO\VLV )RU VLQJOH VWHS JURZWK NLQHWLFV +))V ZHUH LQIHFWHG ZLWK WKH UHVSHFWLYH
235
YLUXVHV7%%$&7%VWRS8/DQG7%UHY ZLWKD02,RIIRUKDW&7KH
236
LQRFXODZHUHUHPRYHGWKHQH[WGD\DQGUHSODFHGZLWKIUHVKPHGLXPDIWHUZDVKLQJZLWK3%6
237
(TXDOLQIHFWLRQUDWHVZHUHFRQWUROOHGE\WLWUDWLRQRIWKHLQRFXODZKLFKZHUHWHUPHG³GD\´
238
6XSHUQDWDQWVIURPYLUXVLQIHFWHGFHOOVZHUHFROOHFWHGHYHU\GD\XQWLOGD\VHYHQDQGVWRUHGDW
239
&9LUXV\LHOGVIURPDWOHDVWIRXULQGLYLGXDOVXSHUQDWDQWVIRUHDFKYLUXVZHUHGHWHUPLQHG
240
RQ+))VE\WLWUDWLRQDVGHVFULEHGSUHYLRXVO\
241
)RFDO YLUXV H[SDQVLRQ ZDV GHWHUPLQHG E\ LQIHFWLQJ FRQIOXHQW +))V ZLWK DQG
242
SODTXHIRUPLQJXQLWV3)8 RIWKHUHVSHFWLYHYLUXVHVIROORZHGE\DQLQFXEDWLRQIRUQLQHGD\V
243
DW&XQGHUDWRPHWK\OFHOOXORVHRYHUOD\7KHRYHUOD\ZDVUHQHZHGRQFHDWGD\
244
ILYHSRVWLQIHFWLRQ)RUWKLVH[SHULPHQWWKHQRWFRPSOHPHQWHG7%VWRSYLUXVZDVXVHG$W
245
GD\ QLQH SRVW LQIHFWLRQ FHOOV ZHUH IL[HG ZLWK PHWKDQRO DQG +&09 LQIHFWHG FHOOV ZHUH
246
YLVXDOL]HGE\LQGLUHFWLPPXQRIOXRUHVFHQFHVWDLQLQJIRUWKH+&09,(DQWLJHQ,PDJHVRI
247
YLUXV LQIHFWHG FHOO IRFL ZHUH DFTXLUHG E\ XVLQJ WKH $[LR2EVHUYHU= FRQIRFDO PLFURVFRSH
248
ZLWKDQ[REMHFWLYHOHQVDQGWKH$[LRYLVLRQVRIWZDUH,(SRVLWLYHQXFOHLIRUHDFKIRFXVRIDW
249
OHDVW IRFL IRU HDFK YLUXV IURP WKUHH LQGHSHQGHQW H[SHULPHQWV ZHUH FRXQWHG E\ XVLQJ WKH
250
PDQXDOFRXQWLQJWRRORIWKHVRIWZDUH$GREH3KRWRVKRS6WDWLVWLFDODQDO\VLVZDVSHUIRUPHGE\
251
DSSO\LQJWKH6WXGHQWWWHVW
252
:HVWHUQ EORWWLQJ )RU ZHVWHUQ EORW DQDO\VLV +))V ZHUH V\QFKURQL]HG IRU K E\ VHUXP
253
VWDUYDWLRQ DQG VXEVHTXHQWO\ LQIHFWHG ZLWK WKH UHVSHFWLYH YLUXVHV DW D 02, RI $W GD\ ILYH
254
SRVW LQIHFWLRQ FHOOV ZHUH ZDVKHG WZLFH ZLWK 3%6 DQG O\VHG LQ 5,3$ EXIIHU $IWHU
255
DGGLWLRQRI [ORDGLQJ EXIIHUFHOOO\VDWHVZHUH VRQLFDWHGIRU PLQ DQGSURWHLQGHQDWXUDWLRQ
10
256
SHUIRUPHG DW & IRU PLQ 7KH O\VDWHV ZHUH WKHQ VXEMHFWHG WR D 6'63$*( DQG
257
WUDQVIHUUHGWRSRO\YLQ\OLGHQHGLIOXRULGH39') PHPEUDQHVIRU:HVWHUQEORWDQDO\VHV
258
9LULRQ JUDGLHQW SXULILFDWLRQ 9LULRQ SXULILFDWLRQ RI 7%%$& 7%8/VWRS DQG 7%
259
8/UHYYLUXVHVZDVSHUIRUPHGHVVHQWLDOO\DVSUHYLRXVO\GHVFULEHG 6XSHUQDWDQWVRI
260
DWOHDVWILYHIXOO\LQIHFWHGFPIODVNVZHUHFROOHFWHGDQGFHOOXODUGHEULVZDVUHPRYHGE\
261
ORZVSHHG FHQWULIXJDWLRQ USP & PLQ 9LUXV SDUWLFOHV ZHUH SHOOHWHG E\
262
XOWUDFHQWULIXJDWLRQIRUKDW&DWUSPLQD6:URWRU%HFNPDQ 3HOOHWHGYLUXV
263
SDUWLFOHVZHUHUHVXVSHQGHGLQPORI0VRGLXPSKRVSKDWHEXIIHUS+ DQGOD\HUHG
264
RQWRJO\FHUROWDUWUDWHJUDGLHQWVIRUPHGLQ0VRGLXPSKRVSKDWH9LUXVSDUWLFOHVZHUHWKHQ
265
VHSDUDWHGE\FHQWULIXJDWLRQIRUPLQDW&DQGUSPLQD6:URWRU7KHYLULRQ
266
OD\HU ZDV YLVXDOL]HG ZLWK LQFDQGHVFHQW OLJKW DQG FROOHFWHG IURP WKH JUDGLHQW 9LULRQV
267
H[WUDFWHG IURP WKH JUDGLHQW ZHUH GLOXWHG ZLWK WKH VRGLXPSKRVSKDWH EXIIHU DQG DJDLQ
268
FHQWULIXJHG DW USP IRU K XVLQJ WKH 6: URWRU 7KH YLULRQV ZHUH SURFHVVHG IRU
269
:HVWHUQEORWDQDO\VLVE\DGGLQJ5,3$EXIIHUDQG[ORDGLQJEXIIHUWRWKHSHOOHW
270
5HDOWLPH 3&59LUDO'1$ZDVLVRODWHG DQGSXULILHGIURPFHOO FXOWXUHVXSHUQDWDQWVDWGD\
271
VHYHQRIVLQJOHVWHSJURZWKNLQHWLFVE\XVLQJWKH+LJK3XUH9LUDO1XFOHLF$FLG.LW5RFKH
272
*HQRPH FRSLHV ZHUH GHWHUPLQHG E\ UHDOWLPH 3&5 ZLWK WKH %ULOOLDQW 43&5 PDVWHU PL[
273
6WUDWDJHQH
274
$**&&*77$&7*7&7*&$**
275
&**&&7&*7$*7*$$$$77$$7**5HODWLYHJHQRPHFRS\QXPEHUVZHUHFDOFXODWHGE\
276
XVLQJDVWDQGDUGFXUYHGHULYHGIURPGHILQHGGLOXWLRQVRI%$&'1$RI7%UHYDQGWKH&W
277
YDOXHVRIWKHWHVWHGYLUDO'1$V5HODWLYHJHQRPLFFRSLHVRI7%%$&ZHUHVHWDW
278
5HDOWLPH3&5ZDVSHUIRUPHGIRUDWOHDVWIRXULQGLYLGXDOVXSHUQDWDQWVIRUHDFKYLUXV
279
7UDQVPLVVLRQ HOHFWURQ PLFURVFRS\ 7KH PHWKRG RI KLJKSUHVVXUH IUHH]LQJ +3) IUHH]H
280
VXEVWLWXWLRQ DQG (SRQ HPEHGGLQJ ZDV SHUIRUPHG DV SUHYLRXVO\ GHVFULEHG ZLWK VOLJKW
281
PRGLILFDWLRQV %ULHIO\+))V[ZHOO ZHUHVHHGHGLQ6OLGHHLJKWZHOOSODWHV
LQFOXGLQJ
6\EU*UHHQ
DQG DQG
11
SULPHUV
+&09
3RO&3)RU
+&093RO&35HY
282
FRQWDLQLQJ FDUERQFRDWHG VDSSKLUH GLVFV PP LQ GLDPHWHU P WKLFNQHVV (QJLQHHULQJ
283
2IILFH 0 :RKOZHQG *PE+ $W D FRQIOXHQFH RI DW OHDVW XVXDOO\ DIWHU RQH GD\ RI
284
FXOWLYDWLRQ FHOOV ZHUH LQIHFWHG ZLWK WKH UHVSHFWLYH YLUXVHV ZLWK DQ 02, EHWZHHQ DQG
285
)LYH GD\V SRVW LQIHFWLRQ FHOOV RQ VDSSKLUH GLVFV ZHUH IL[HG E\ +3) XVLQJ WKH &RPSDFW
286
KLJKSUHVVXUHIUHH]HU(QJLQHHULQJ2IILFH0:RKOZHQG*PE+ 7KHUHPDLQLQJFHOOVLQWKH
287
6OLGH HLJKWZHOO SODWH ZHUH IL[HG ZLWK SDUDIRUPDOGHK\GH IRU PLQ DW & DQG
288
VXEMHFWHGWRLQGLUHFWLPPXQRIOXRUHVFHQFHVWDLQLQJWRFRQWUROIRULQIHFWLRQUDWHVDQGLISRVVLEOH
289
IRUPXWDQWYLUXVW\SLFDODOWHUDWLRQV$IWHU+3)FHOOVRQWKHVDSSKLUHGLVFVZHUHVXEMHFWHGWR
290
IUHH]HVXEVWLWXWLRQ DQG VXEVHTXHQWO\ HPEHGGHG LQ (SRQ )OXND )RU WUDQVPLVVLRQ
291
HOHFWURQPLFURVFRS\7(0 XOWUDWKLQVHFWLRQVZHUHFXWDWDQXOWUDPLFURWRPH8OWUDFXW8&7
292
/HLFD SODFHG RQ IRUPYDU FRDWHG VLQJOH VORW JULGV PP [ PP VORW GLPHQVLRQV 3ODQR
293
*PE+ DQGH[DPLQHGLQD-HRO-(0WUDQVPLVVLRQHOHFWURQPLFURVFRSHHTXLSSHGZLWKD
294
&&'FDPHUDDWDQDFFHOHUDWLRQYROWDJHRIN9
295
4XDQWLWDWLYH DQDO\VHV E\ 7(0 0RUSKRJHQHVLV VWDJHV RI YLUXV SDUWLFOHV LQ WKH DUHD RI WKH
296
Y$& ZHUH TXDQWLILHG DV SUHYLRXVO\ GHVFULEHG LQ WZRGLPHQVLRQDO HOHFWURQ PLFURJUDSKV
297
WKDW ZHUH WDNHQ IURP UDQGRPO\ VHOHFWHG LQIHFWHG FHOOV IURP DW OHDVW WKUHH LQGHSHQGHQW
298
H[SHULPHQWV IRU HDFKYLUXV2QO\ FHOOV ZHUH TXDQWLILHG WKDW KDG PRUH WKDQ WHQDQG OHVVWKDQ
299
SDUWLFOHVDWWKHDUHDRIWKHY$&)RUHDFKDQDO\]HGFHOOWKHQXPEHUVRIWKHYDULRXVYLUXV
300
SDUWLFOHV ZHUH GHWHUPLQHG IURP DW OHDVW IRXU PLFURJUDSKV ZKLFK WRJHWKHU FRYHUHG WKH HQWLUH
301
DUHDRIWKHY$&0LFURJUDSKVZHUHWDNHQDWDPDJQLILFDWLRQRI[ZKLFKZDVVXIILFLHQW
302
WRGLVWLQJXLVKWKHYDULRXVPRUSKRJHQHVLVVWDJHVRIYLUXVSDUWLFOHV
303
5HVXOWV
304
*URZWKFKDUDFWHULVWLFVRIDQHZO\JHQHUDWHGUL47VWRSPXWDQWYLUXV
305
$UROHRIS8/IRUWKHJHQHUDWLRQRILQIHFWLRXVYLUXVSDUWLFOHVDQGGXULQJYLUDOHQWU\SULRUWR
306
LPPHGLDWH HDUO\ ,( JHQH H[SUHVVLRQ KDV EHHQ VKRZQ SUHYLRXVO\ IRU D PXWDQW RI $'
307
ODFNLQJ PRVW RI WKH UL47 VHTXHQFH 7R HOXFLGDWH WKH H[DFW IXQFWLRQ RI S8/ GXULQJ 12
308
+&09 PRUSKRJHQHVLV HVSHFLDOO\ LQ WKHODWH VWDJHV RI YLULRQ DVVHPEO\ D QHZ PXWDQW YLUXV
309
7%VWRS ZDV JHQHUDWHG LQ WKH EDFNERQH RI DQ LQIHFWLRXV FORQH 7%%$& RI WKH
310
HQGRWKHOLRWURSLF+&09VWUDLQ7%( 7RPLQLPL]HXQZDQWHGHIIHFWVRQWKHH[SUHVVLRQ
311
RI QHLJKERULQJ JHQHV D VWRS FRGRQ ZDV JHQHUDWHG DW DPLQR DFLG SRVLWLRQ E\ LQWURGXFLQJ
312
VXEVWLWXWLRQVRIQXFOHRWLGHV$7DQG7$RIWKHUL47RSHQUHDGLQJIUDPH25) )LJ$
313
7KH VWRS FRGRQ LV IROORZHG E\ D GHOHWLRQ RI QXFOHRWLGH * FDXVLQJ D IUDPHVKLIW WR
314
FRPSOHWHO\ SUHYHQW H[SUHVVLRQ RI S8/ 7KHVH PXWDWLRQV ZHUH LQWURGXFHG GRZQVWUHDP RI
315
WKHUL4625)$UHYHUWDQWYLUXV7%UHYZDVJHQHUDWHGE\PXWDWLQJWKHUL47VHTXHQFH
316
RI7%VWRSEDFNWRWKHRULJLQDOVHTXHQFH7KHDGGLWLRQDOLQWURGXFWLRQRIWKHPXWDWLRQ$7
317
LQUL47UHVXOWHGLQDVLOHQWPXWDWLRQLQS8/RIWKH7%UHYYLUXVZKLFKDOORZVGLVWLQFWLRQ
318
RI WKH UHYHUWDQW YLUXV IURP SDUHQWDO 7%%$& 'XULQJ UHFRQVWLWXWLRQ RI WKH 7%VWRS
319
YLUXV ZH QRWLFHG D VHYHUHO\ LPSDLUHG JURZWK LQ FHOO FXOWXUH DFFRPSDQLHG ZLWK LQVXIILFLHQW
320
H[WUDFHOOXODUYLUXV\LHOGVIRUKLJK02,LQIHFWLRQV7RFRPSOHPHQWIRUWKHJURZWKLPSDLUPHQW
321
7%VWRSYLUXVZDVSURSDJDWHGLQS8/H[SUHVVLQJ05&FHOOVGHVLJQDWHGDVW05&
322
0XWDQWYLUXVSURSDJDWHGRQW05&7%VWRS8/ LVSKHQRW\SLFDOO\FRPSOHPHQWHGEXW
323
XQDEOHWRH[SUHVVS8/IURPWKHYLUDOJHQRPHGDWDQRWVKRZQ :HILUVWGHWHUPLQHGIRFDO
324
VSUHDG RI RXU 7%VWRS YLUXV E\ SHUIRUPLQJ D IRFXV H[SDQVLRQ DVVD\)LJ 5HPDUNDEO\
325
IRFDO VSUHDG RI WKH 7%VWRS YLUXV LQ +)) ZDV DOPRVW DEURJDWHG VLQFH PDQ\ VLQJOH
326
LPPHGLDWHHDUO\ ,( SRVLWLYH FHOOV DQG RQO\ YHU\ VPDOO IRFL ZLWK D PD[LPXP RI HLJKW ,(
327
SRVLWLYH FHOOV ZHUH FRXQWHG DW QLQH GD\V SRVW LQIHFWLRQ ,Q FRQWUDVW ZLOGW\SH 7%%$&
328
DQG UHYHUWDQW YLUXVHV H[KLELWHG IRFL ZLWK D PHGLDQ QXPEHU RI HLJKW\ ,(SRVLWLYH FHOOV 7KLV
329
LPSOLHVWKDWIRFDOVSUHDGRI+&09UHTXLUHVS8/:HWKHQFRPSDUHGYLUDOJURZWKRI7%
330
VWRSYLUXVWRWKDWRI7%UHYDQGZLOGW\SH7%%$&YLUXVHVLQDVLQJOHVWHSJURZWK
331
NLQHWLFE\LQIHFWLQJILEUREODVWVDWDQ02,RI)LJ$ ,QIHFWLRQZLWKWKH7%VWRSYLUXV
332
UHVXOWHGLQXSWRIROGORZHUYLUXV\LHOGVLQVXSHUQDWDQWVRILQIHFWHGILEUREODVWVFRPSDUHG
333
WRWKRVHLQIHFWHGZLWK7%%$&DQGUHYHUWDQWYLUXVHV&RPSDUDEOHJURZWKRI7%%$& 13
334
DQG 7%UHY YLUXVHV LQGLFDWHG WR XV WKDW WKH PXWDWLRQ RI 7%VWRS ZDV VXFFHVVIXOO\
335
UHVWRUHG LQ WKH UHYHUWDQW YLUXV *LYHQ WKH SUHYLRXVO\ UHSRUWHG LPSDLUHG LQIHFWLYLW\ RI YLUXV
336
SDUWLFOHV LQ DEVHQFH RI S8/ ZH WHVWHG WR ZKLFK H[WHQW WKLV FRQWULEXWHG WR WKH ORZHU
337
YLUXV \LHOGV LQ VLQJOH VWHS JURZWK NLQHWLFV E\ GHWHUPLQLQJ WKH SDUWLFOHWR3)8 UDWLRV IRU DOO
338
WKUHH YLUXVHV :H XVHG WKH FXOWXUH VXSHUQDWDQWV RI VLQJOH VWHS JURZWK NLQHWLFV DW GD\ VHYHQ
339
SRVW LQIHFWLRQ DQG DQDO\]HG WKHP LQ WZR GLIIHUHQW ZD\V ,QIHFWLRXV YLUXV \LHOGV ZHUH
340
GHWHUPLQHGE\WLWUDWLRQDQGYLUDOJHQRPHFRSLHVZHUHTXDQWLILHGIURPHTXDOYROXPHVRIWKHVH
341
VXSHUQDWDQWV E\ UHDOWLPH 3&5 7KH UHODWLYH JHQRPH FRS\ QXPEHUV ZHUH FDOFXODWHG IURP D
342
VWDQGDUGFXUYHDQGWKHQXPEHURIJHQRPLFFRSLHVRI7%%$&YLUXVZDVVHWDW:H
343
IRXQGOHVVYLUDO'1$LQVXSHUQDWDQWVIURP7%VWRSLQIHFWHGFHOOVLQFRPSDULVRQWR7%
344
%$&YLUXVLQIHFWHGFHOOVZKHUHDV7%UHYDQG7%%$&YLUXVHVUHOHDVHGFRPSDUDEOH
345
'1$ OHYHOV )LJ% 5HODWLYH LQIHFWLYLW\ LV H[SUHVVHG DV WKH UDWLR EHWZHHQ WKH UHODWLYH
346
JHQRPHFRS\QXPEHUDQGWKHYLUXV\LHOGLQWKHVXSHUQDWDQW)LJ& 7KHFRPSDULVRQRIWKH
347
WKUHHYLUXVHVUHYHDOHGDIROGORZHUUHODWLYHLQIHFWLYLW\RIYLUXVSDUWLFOHVUHOHDVHGIURP7%
348
VWRSYLUXVLQIHFWHGFHOOVLQGLFDWLQJDQLPSRUWDQWUROHRIS8/LQSURGXFWLRQRILQIHFWLRXV
349
YLUXVSURJHQ\,QFRQWUDVWWRWKH$'EDVHGPXWDQWYLUXVZHIRXQGOHVVJHQRPHVUHOHDVHG
350
IURP 7%VWRS YLUXV LQIHFWLRQV ZKLFK VXJJHVWV WKDW HLWKHU IRUPDWLRQ RU HJUHVV RI YLUXV
351
SDUWLFOHVUHTXLUHVS8/
352
7%VWRSH[KLELWVDGHIHFWLQYLULRQPRUSKRJHQHVLV
353
7RLQYHVWLJDWHSRVVLEOH GHIHFWV LQODWHVWDJHVRIYLUXV PRUSKRJHQHVLVZHSHUIRUPHG HOHFWURQ
354
PLFURVFRSLF LQYHVWLJDWLRQ RI 7%VWRS LQIHFWHG FHOOV DW ILYH GD\V SRVW LQIHFWLRQ )LUVW ZH
355
FRQFHQWUDWHG RQ WKH XOWUDVWUXFWXUH RI LQWUD DQG H[WUDFHOOXODU 7%VWRS YLUXV SDUWLFOHV LQ
356
FRPSDULVRQ WR WKRVH RI ZLOGW\SH YLUXV 7%%$& DQG WKH UHYHUWDQW YLUXV VLQFH WKH
357
LPSDLUHGLQIHFWLYLW\RI7%VWRSSDUWLFOHVFRXOGEHEDVHGRQDOWHUDWLRQVRIWKHWHJXPHQW7KH
358
XOWUDVWUXFWXUH RI LQWUDFHOOXODU DQG H[WUDFHOOXODU YLULRQV )LJ HVSHFLDOO\ WKH WKLFNQHVV DQG
359
DSSHDUDQFH RI WKH WHJXPHQW OD\HU ZDV XQGLVWLQJXLVKDEOH EHWZHHQ DOO WKUHH YLUXVHV DUJXLQJ 14
360
DJDLQVW D PDMRU UROH RI S8/ IRU WHJXPHQW IRUPDWLRQ 1H[W ZH ORRNHG DW QXFOHDU DQG
361
F\WRSODVPLFVWDJHVRIYLUXVPRUSKRJHQHVLVWRGHWHUPLQHLIWKHUHZDVDGHIHFWDFFRXQWLQJIRU
362
WKHLPSDLUPHQWLQYLUXVUHOHDVH1XFOHDUVWDJHVRI+&09PRUSKRJHQHVLVDSSHDUHGQRUPDOLQ
363
7%VWRS YLUXV LQIHFWHG FHOOV DV WKH VWUXFWXUH DQG UDWLRV RI $ % DQG &FDSVLGV ZHUH
364
XQGLVWLQJXLVKDEOHIRUDOOWKUHHYLUXVHVGDWDQRWVKRZQ 7RFODULI\ZKHWKHUWKHJURZWKGHIHFW
365
RI WKH 7%VWRS YLUXV ZDV EDVHG RQ GHIHFWLYH VHFRQGDU\ HQYHORSPHQW ZH GHWHUPLQHG WKH
366
UDWLR RI IXOO\ HQYHORSHG FDSVLGV PHPEUDQH DWWDFKHG FDSVLGV DQG FDSVLGV ZLWK QR FRQWDFW WR
367
PHPEUDQHV QDNHG LQ WKH Y$&V RI LQIHFWHG ILEUREODVWV 7DEOH :H LQFOXGHG LQ RXU
368
TXDQWLILFDWLRQRQO\FHOOVWKDWVKRZHGDVLPLODUGHQVLW\RIQXFOHDUFDSVLGVWRHQVXUHDVLPLODU
369
VWDJH RI LQIHFWLRQ 2WKHU WKDQ FHOOV ODFNLQJ DQ\ SDUWLFOHV DVVRFLDWHG ZLWK WKH Y$& DW OHDVW
370
VHYHQ 7%VWRS YLUXV LQIHFWHG FHOOV ZH IRXQG DQ LQFUHDVH RI QRQHQYHORSHG FDSVLGV LQ
371
Y$&VRIWKH7%VWRSYLUXV)LJ$7DEOH 1XPEHUVRIIXOO\HQYHORSHGSDUWLFOHVZHUH
372
VOLJKWO\UHGXFHGLQWKHDEVHQFHRIS8/1HYHUWKHOHVVWKHPDMRULW\RIYLUXVSDUWLFOHVLQWKH
373
DUHDRIWKHY$&ZHUHIXOO\HQYHORSHG&RQVLVWHQWZLWKWKLVZHIUHTXHQWO\IRXQGYLULRQVLQWKH
374
H[WUDFHOOXODUVSDFHRI7%VWRSYLUXVLQIHFWHGFHOOV)LJ%
375
7KH PRVW REYLRXV SKHQRW\SLF DOWHUDWLRQ LQ FHOOV LQIHFWHG ZLWK 7%VWRS YLUXV ZDV WKDW LQ
376
PDQ\ 7%VWRS YLUXV LQIHFWHG FHOOV D ODUJH TXDQWLW\ RI QRQHQYHORSHG YLUXV FDSVLGV
377
DFFXPXODWHG LQ WKH FHOO SHULSKHU\ )LJ$ 7KHVH DFFXPXODWLRQV ZHUH GHQVHO\ SDFNHG ZLWK
378
PDLQO\&FDSVLGVDQGDIHZHPSW\FDSVLGV7KHHOHFWURQGHQVH PDWHULDOWKDWZDVGHFRUDWLQJ
379
WKH RXWVLGH RI WKHVH FDSVLGV DSSHDUHG WR EH GLIIHUHQW LQ GHQVLW\ DQG WKLFNQHVV IURP WKH
380
FODVVLFDO WHJXPHQW VWUXFWXUH RI IXOO\ HQYHORSHG YLULRQV IRXQG DW WKH Y$& )LJ$ KLJKHU
381
PDJQLILFDWLRQRIFDSVLGV :HLQWHUSUHWWKLVDVDUHVXOWRIDGHIHFWLQDFTXLVLWLRQRIWKHQRUPDO
382
WHJXPHQW
383
,QFRQFOXVLRQRXUXOWUDVWUXFWXUDOGDWDVXJJHVWWKDWWHJXPHQWDWLRQDQGVHFRQGDU\HQYHORSPHQW
384
FDQSURFHHGZLWKRXWS8/EXWF\WRSODVPLFWUDIILFNLQJRIFDSVLGVVHHPVWREHDOWHUHGLQWKH
15
385
DEVHQFHRIS8/$VDUHVXOWQRQHQYHORSHGFDSVLGVDFFXPXODWHDWWKHSHULSKHU\RIWKHFHOO
386
$OOWKHVHDOWHUDWLRQVOLNHO\FRQWULEXWHWRWKHJURZWKLPSDLUPHQWRI7%VWRSYLUXV
387
,QWUDFHOOXODUGLVWULEXWLRQRIYLUDOSURWHLQVLQDEVHQFHRIS8/
388
7R VXSSRUW WKH XOWUDVWUXFWXUDO GLIIHUHQFHV LQ 7%VWRS YLUXV LQIHFWHG FHOOV ZH LQYHVWLJDWHG
389
WKH LQWUDFHOOXODU GLVWULEXWLRQ RI YLUDO SURWHLQV LQ WKH DEVHQFH RI S8/ )XUWKHUPRUH ZH
390
VRXJKWWRLGHQWLI\WHJXPHQWSURWHLQVZKLFKFDQELQGWRFDSVLGVLQGHSHQGHQWO\RIS8/:H
391
K\SRWKHVL]HG WKDW PRVW OLNHO\ SURWHLQV RI WKH LQQHU WHJXPHQW ZLOO EH GHWHFWHG DW FDSVLG
392
DFFXPXODWLRQV RI 7%VWRS YLUXV LQIHFWHG FHOOV 7KHUHIRUH ZH SHUIRUPHG LQGLUHFW
393
LPPXQRIOXRUHVFHQFH VWDLQLQJV IRU WHJXPHQW SURWHLQV SS UL32 DQG S8/ +&09
394
SS LV NQRZQ WR GLUHFWO\ LQWHUDFW ZLWK FDSVLGV DQG WR EH LQYROYHG LQ VWDELOL]LQJ
395
FDSVLGV ,WKDVDOVREHHQXVHGDVD PDUNHUWRVWXG\LQWUDFHOOXODUFDSVLGWUDIILFNLQJ
396
:HK\SRWKHVL]HGWKDWSSELQGLQJWRFDSVLGVLVLQGHSHQGHQWRIS8/EHFDXVHLWLVQRWSDUW
397
RIWKHS8/S8/0&3S8/FRPSOH[ DQGOLNHO\DWWDFKHVWRFDSVLGVLQWKHQXFOHXV
398
%\VWDLQLQJIRUS8/ZHZDQWHGWRFODULI\ZKHWKHUS8/UHJXODWHVDWWDFKPHQWRI
399
S8/ WR FDSVLGV 6WDLQLQJ IRU WHJXPHQW SURWHLQ SS ZDV LQFOXGHG EHFDXVH WKLV SURWHLQ LV
400
VWURQJO\ ORFDOL]HG WR WKH Y$& GXULQJ WKH HQWLUH FRXUVH RI LQIHFWLRQ DQG PRVW OLNHO\
401
LQFRUSRUDWHGLQWRYLULRQVWKHUH ,QGLUHFWLPPXQRIOXRUHVFHQFHDQDO\VLVZDVSHUIRUPHG
402
RQ LQIHFWHG FHOOV WKDW ZHUH LGHQWLFDOO\ WUHDWHG DV WKRVH XVHG IRU HOHFWURQ PLFURVFRSLF
403
LQYHVWLJDWLRQV 7KH PDMRULW\ RI 7%%$& DQG 7%UHY LQIHFWHG ILEUREODVWV H[KLELWHG
404
FRQFHQWUDWHG VLJQDOV IRU SS S8/ DQG SS DW WKH DUHD RI WKH Y$& DW ILYH GD\V SRVW
405
LQIHFWLRQ )LJ$ %\ FRQWUDVW LQ 7%VWRS LQIHFWHG ILEUREODVWV SS VLJQDOV ZHUH IRXQG
406
SUHGRPLQDQWO\DWWKHQXFOHRFDSVLGDFFXPXODWLRQVLQWKHFHOOSHULSKHU\7KHSUHVHQFHRIYLUDO
407
'1$DWWKHVHDFFXPXODWLRQVZDVLQGLFDWHGE\'$3,VLJQDOV7KHVHDFFXPXODWLRQVZHUHDOVR
408
SRVLWLYHIRUS8/EXWGHYRLGRISSZKLFKUHPDLQHGORFDOL]HGDWWKHY$&7KLVVXJJHVWHG
409
WRXVWKDWDWWDFKPHQWRIERWKSSDQGS8/GRHVQRWUHTXLUHS8/,QDJUHHPHQWZLWK
410
RXU XOWUDVWUXFWXUDO GDWD ZH QRWHG WKDW WKH LQWUDFHOOXODU GLVWULEXWLRQ RI SS LQ 7%VWRS 16
411
YLUXV LQIHFWHG FHOOV H[KLELWHG YDULRXV SDWWHUQV )LJ% ,Q DEVHQFH RI S8/ VLJQDOV IRU
412
SS VLJQDOV ZHUH HLWKHU VWULFWO\ ORFDOL]HG DW WKH FHOO SHULSKHU\ D SKHQRW\SH WKDW ZDV
413
UHVWULFWHGWRWKH7%VWRSYLUXVRUDWWKHY$&RUDWERWKVLWHV)LJ $TXDQWLILFDWLRQRI
414
WKHVH SKHQRW\SHV RI YLUXV LQIHFWHG FHOOV DW ILYH GD\V SRVW LQIHFWLRQ VKRZHG WKDW WKH
415
FRQFHQWUDWLRQRISSVLJQDOVDWWKHY$&ZDVWKHSUHGRPLQDQWSKHQRW\SHLQZLOGW\SHDQG
416
UHYHUWDQW YLUXV LQIHFWHG FHOOV )LJ& %\ FRQWUDVW WKH PRVW DEXQGDQW SKHQRW\SH LQ 7%
417
VWRSYLUXVLQIHFWHGFHOOVZDVFKDUDFWHUL]HGE\DQDFFXPXODWLRQRISSVLJQDOVDWWKHFHOO
418
SHULSKHU\ WRJHWKHU ZLWK VLJQDOV DW WKH Y$& ,Q FRQFOXVLRQ WKH TXDQWLILFDWLRQ RI SS
419
SKHQRW\SHVVXSSRUWVWKHUHVXOWIURPXOWUDVWUXFWXUDOGDWDWKDWS8/KDVDQLPSRUWDQWUROHLQ
420
FDSVLGWUDIILFNLQJDQGWHJXPHQWDWLRQ
421
$QDO\VLVRI7%VWRSLQIHFWHGFHOOVLQWUDFHOOXODUSURWHLQVDQGYLULRQFRPSRVLWLRQ
422
,QFRUSRUDWLRQ RI PDQ\ YLUDO SURWHLQV LQWR YLULRQV KDV EHHQ VKRZQ WR EH UHJXODWHG E\ WKHLU
423
LQWHUDFWLRQ ZLWK RWKHU YLUDO SURWHLQV %HFKWHO DQG 6FKHQN VKRZHG DQ RYHUDOO
424
GHFUHDVHRIS8/OHYHOVLQLQIHFWHGFHOOVDQGDQLPSDLUHGYLULRQLQFRUSRUDWLRQLQDEVHQFHRI
425
S8/ 7KHUHIRUH ZHH[DPLQHGWKHFRPSRVLWLRQRIH[WUDFHOOXODU YLULRQVUHOHDVHGIURP
426
7%VWRS YLUXV LQIHFWHG FHOOV $V VKRZQ LQ )LJ GHWHFWLRQ RI S8/ ZLWK RXU SRO\FORQDO
427
DQWLERG\GLUHFWHGDJDLQVWDUHJLRQFRPSULVLQJDPLQRDFLGVWRYHULILHGWKDWWKHVWRS
428
FRGRQ LQ 7%VWRS YLUXV LQGHHGSUHYHQWHG H[SUHVVLRQ RI S8/&RQVLVWHQWO\ S8/ ZDV
429
QRWGHWHFWHGLQSXULILHG7%VWRSYLULRQV'HWHFWLRQRIS8/UHYHDOHGUHGXFHGOHYHOVLQFHOO
430
O\VDWHVDVZHOODVLQSXULILHGYLULRQV,QFRQWUDVWOHYHOVRIRWKHUWHVWHGYLUDOSURWHLQVS8/
431
0&3 S8/SS S8/SS S8/SS DQGS8/SS LQYLULRQVDQGFHOO
432
O\VDWHVZHUHVLPLODULQ7%VWRSFRPSDUHGWR7%%$&DQG7%UHYYLUXVHV7KHRQO\
433
H[FHSWLRQZDVWHJXPHQWSURWHLQS8/ZKRVHSUHVHQFHLQYLULRQVZDVFOHDUO\UHGXFHGZKLOH
434
LQWUDFHOOXODUOHYHOVRIWKLVSURWHLQDSSHDUHGWREHXQDIIHFWHGLQDEVHQFHRIS8/7KXV7%
435
VWRS YLULRQV ZHUH GHILFLHQW IRU S8/ DQG FRQWDLQHG UHGXFHG DPRXQWV RI S8/ DQG
436
S8/ 17
437
/RFDOL]DWLRQRIS8/GXULQJLQIHFWLRQ
438
+DYLQJ VKRZQ DQ LPSRUWDQW UROH RI S8/ IRU WKH WHJXPHQWDWLRQ DQG SDUWLFOH WUDIILFNLQJ
439
GXULQJ LQIHFWLRQ ZH VRXJKW WR GHWHUPLQH WKH LQWUDFHOOXODU ORFDOL]DWLRQ RI WKLV SURWHLQ LQ
440
LQIHFWLRQ 'XH WR WKH ODFN RI DQ DQWLERG\ GHWHFWLQJ S8/ LQ LQGLUHFW LPPXQRIOXRUHVFHQFH
441
ZH JHQHUDWHG WZR PXWDQW YLUXVHV WKDW H[SUHVV S8/ ZLWK HLWKHU DQ 1WHUPLQDO RU D &
442
WHUPLQDO)ODJWDJGHVLJQDWHG7%1IODJDQG7%&IODJUHVSHFWLYHO\)LJ% *URZWKRI
443
WKHVHPXWDQWVZDVDQDO\]HGLQDPXOWLVWHSJURZWKNLQHWLFWRYHULI\WKDWWKH)ODJWDJLQVHUWLRQV
444
LQ UL47 GLG QRW DIIHFW YLUDO JURZWK %RWK PXWDQW YLUXVHV UHDFKHG H[WUDFHOOXODU YLUXV \LHOGV
445
WKDWZHUHFRPSDUDEOHWRWKRVHRISDUHQWDOYLUXV)LJ$ 6XEVHTXHQW:HVWHUQEORWDQDO\VLVRI
446
LQIHFWHGFHOOO\VDWHVDWGD\ILYHSRVWLQIHFWLRQVKRZHGVLPLODUSURWHLQOHYHOVIRUERWK)ODJWDJ
447
YHUVLRQV RI S8/ )LJ% :H DOVR FKHFNHG S8/ OHYHOV WR H[FOXGH HIIHFWV RQ LWV
448
H[SUHVVLRQ FDXVHG E\ WKH )ODJWDJ LQVHUWLRQ GLUHFWO\ LQ IURQW RI WKH VWDUW RI S8/ LQ 7%
449
&IODJ $V VKRZQ LQ )LJ% O\VDWHV RI 7%&IODJ LQIHFWHG FHOOV H[KLELWHG UHSHDWHGO\
450
UHGXFHGOHYHOVRIS8/FRPSDUHGWRFHOOO\VDWHVRI7%1IODJDQGSDUHQWDOYLUXVLQIHFWLRQ
451
$WWKHOLJKWRIWKHVHUHVXOWVZHSULPDULO\XVHGWKH7%1IODJPXWDQWIRUWKHGHWHUPLQDWLRQ
452
RI S8/ ORFDOL]DWLRQ GXULQJ LQIHFWLRQ *LYHQ WKH LQWHUDFWLRQ RI S8/ ZLWK S8/ LQ
453
WUDQVIHFWLRQ DQG LQ LQIHFWLRQ ZH K\SRWKHVL]HG WKDW WKH LQWUDFHOOXODU GLVWULEXWLRQ RI
454
S8/LVVLPLODUWRWKDWRIS8/WKHODWWHUKDVEHHQVKRZQWRDFFXPXODWHDWWKHY$&
455
7RDGGUHVV WKLVLQWUDFHOOXODUGLVWULEXWLRQRIERWKS8/DQGS8/ZDVDQDO\]HG DWHDUO\
456
WKUHHGD\VSRVWLQIHFWLRQ DQGODWHILYHGD\VSRVWLQIHFWLRQ WLPHVRILQIHFWLRQ6LQFHLQIHFWHG
457
FHOOVDWWKUHHGD\VSRVWLQIHFWLRQH[KLELWHGGLIIHUHQWVWDJHVRILQIHFWLRQZHVHOHFWHGIRUFHOOV
458
ZLWKWKHOHDVWDGYDQFHGVWDJH7KHVHFHOOVZHUHFKRVHQIRUDSUHPDWXUHY$&DQGWKHODFNRI
459
'$3, VLJQDOV DW WKLV VLWH &HOOV RI WKLV VWDJH DOVR ODFNHG SS VLJQDOV DW WKH VLWH RI WKH
460
SUHPDWXUH Y$& LQGLFDWLQJ IRU DQ DEVHQFH RI YLUXV SDUWLFOHV GDWD QRW VKRZQ $V VKRZQ LQ
461
)LJ&S8/1IODJH[KLELWHGDVLPLODUORFDOL]DWLRQSDWWHUQDVS8/DQGWHJXPHQWSURWHLQ
462
SS7KHLUVLJQDOVZHUHIRXQGSUHGRPLQDQWO\SHULQXFOHDUDWWKHVLWHRIWKHSUHPDWXUHY$& 18
463
7KH ODFN RI VLJQDOV IRU FDSVLGDVVRFLDWHG SS LQ WKH F\WRSODVP RI FHOOV DW WKLV VWDJH RI
464
LQIHFWLRQGDWDQRWVKRZQ LQGLFDWHGWKDWWKHREVHUYHGS8/ORFDOL]DWLRQ LVLQGHSHQGHQWRI
465
FDSVLGV$WILYHGD\VSRVWLQIHFWLRQS8/VLJQDOVVWURQJO\RYHUODSSHGZLWKWKRVHRIS8/
466
DQG'$3,VLJQDOVDWWKHY$&EXWVKRZHGRQO\DSDUWLDORYHUODSZLWKSSVLJQDOV7KHVHGDWD
467
DUHFRQVLVWHQWZLWKWKHIRUPDWLRQRIDS8/S8/FRPSOH[DQGWKHDFFXPXODWLRQRIYLUXV
468
SDUWLFOHVDWWKHY$&
469
/RFDOL]DWLRQRIS8/LVGHWHUPLQHGE\S8/
470
%HFDXVH RI WKH LQWHUDFWLRQ RI S8/ZLWK S8/DQG WKHLUFRORFDOL]DWLRQ GXULQJ LQIHFWLRQ
471
ZHVRXJKWWRGHWHUPLQHWKHUROHRIS8/IRULQWUDFHOOXODUORFDOL]DWLRQRIS8/7KHUHIRUH
472
ZH XVHG LQ LQGLUHFW LPPXQRIOXRUHVFHQFH DQDO\VLV WKH 7%&IODJ YLUXV ZKLFK VKRZHG
473
UHGXFHG OHYHOV RI S8/ LQ :HVWHUQ EORW DQDO\VLV DQG DOORZV GHWHFWLRQ RI S8/ E\ D &
474
WHUPLQDO )ODJWDJ $V VKRZQ LQ )LJ$ WKH PDMRULW\ RI S8/&IODJ ZDV GHWHFWHG LQ WKH
475
QXFOHXV DQG RQO\ YHU\ OLWWOH DW WKH VLWH RI WKH Y$& LQ LQIHFWLRQV ZLWK WKH 7%&IODJ YLUXV
476
ZKHUHDV S8/ ZDV VWLOO IRXQG DW WKH VLWH RI WKH Y$& 7KHVH FKDQJHV LQ LQWUDFHOOXODU
477
GLVWULEXWLRQRIS8/ZHUHREVHUYHGLQWKHPDMRULW\RILQIHFWHGFHOOVDWHDUO\DQGODWHWLPHVRI
478
LQIHFWLRQ )LQDOO\ ZH GHWHUPLQHG ORFDOL]DWLRQ RI S8/ LQ WUDQVIHFWHG FHOOV 7UDQVLHQW
479
H[SUHVVLRQLQ+H/DFHOOVVKRZHGDVWURQJQXFOHDUORFDOL]DWLRQRIS8/LQDEVHQFHRIRWKHU
480
YLUDO SURWHLQV )LJ% &RQVLGHULQJ WKH PROHFXODU ZHLJKW RI DSSUR[LPDWHO\ N'D WKDW
481
H[FOXGHVIUHHGLIIXVLRQWKURXJKQXFOHDUSRUHVS8/DSSHDUVWREHDFWLYHO\WUDQVSRUWHGLQWR
482
WKHQXFOHXV7KHVHGDWDVXJJHVWWKDWGXULQJLQIHFWLRQS8/LVWUDQVORFDWHGIURPWKHQXFOHXV
483
WRWKHY$&DVIRXQGIRU7%1IODJLQIHFWLRQDQGWKDWLWIDLOVWUDQVORFDWLRQLQFHOOVLQIHFWHG
484
ZLWKWKH7%&IODJYLUXV
485
'LVFXVVLRQ
486
,QWKLVVWXG\ZHKDYHDQDO\]HGIXQFWLRQVRIWKH+&09WHJXPHQWSURWHLQS8//LWWOHZDV
487
NQRZQDERXWLWVIXQFWLRQGXULQJ+&09PRUSKRJHQHVLVHYHQWKRXJKLWLVDKLJKO\FRQVHUYHG
488
WHJXPHQWSURWHLQDPRQJKHUSHVYLUXVHV ZLWKFHQWUDOWRHVVHQWLDOUROHVIRUWKHJHQHUDWLRQRI 19
489
LQIHFWLRXVSURJHQ\LQDOSKDKHUSHVYLUXVHV $SUHYLRXVFKDUDFWHUL]DWLRQRIDQ$'
490
EDVHGPXWDQWYLUXVZLWKDODUJHVXEVWLWXWLRQRIWKHUL4725)UHYHDOHGDQLPSRUWDQWIXQFWLRQ
491
HDUO\ LQ +&09 LQIHFWLRQ 7KH VDOLHQW ILQGLQJ RI RXU VWXG\ LV WKDW S8/ KDV DOVR DQ
492
LPSRUWDQWIXQFWLRQGXULQJYLULRQPRUSKRJHQHVLVDQGWKHUHLQWKHSURFHVVRIWHJXPHQWDWLRQRI
493
FDSVLGV)XUWKHUPRUHZHVKRZWKDWS8/LVDFFXPXODWLQJDWWKHY$&WRJHWKHUZLWKS8/
494
DQGWKDWWKLVDFFXPXODWLRQLVUHJXODWHGE\S8/
495
7KHDEVHQFHRIS8/UHVXOWVLQDVHYHUHJURZWKGHIHFWZLWKORZHUH[WUDFHOOXODUYLUXVWLWHUV
496
DQG LPSDLUHG IRFDO VSUHDG $ SUHYLRXVO\ FKDUDFWHUL]HG UL47VXEVWLWXWLRQ PXWDQW VKRZHG
497
LPSDLUHGUHSOLFDWLRQLQILEUREODVWVDQGDQLQFUHDVHGSDUWLFOHWR3)8UDWLRWRJHWKHUZLWKDGHOD\
498
LQWKHRQVHWRIYLUDOJHQHH[SUHVVLRQ ,QWKLVVWXG\ZHHYDOXDWHGYLUDOJURZWKLQDEVHQFH
499
RI S8/ LQ WKH JHQHWLF EDFNJURXQG RI DQ LQIHFWLRXV FORQH RI WKH HQGRWKHOLRWURSLF +&09
500
VWUDLQ7%( 'XHWRWKHFRPSOH[RUJDQL]DWLRQRIWKHUL47UHJLRQDQGWRPLQLPL]HWKH
501
ULVNRIDIIHFWLQJH[SUHVVLRQRIQHLJKERULQJJHQHVDPXWDQWYLUXV7%VWRS ZDVJHQHUDWHG
502
LQZKLFKH[SUHVVLRQRIS8/ZDVDEURJDWHGE\LQVHUWLRQRIDVWRSFRGRQ:HREVHUYHGXSWR
503
IROGORZHUQXPEHUVRILQIHFWLRXVSDUWLFOHVLQWKHVXSHUQDWDQWRI7%VWRSLQIHFWHGFHOOV
504
)LJ$ DQG FRQILUPHG ZLWK WKLV YLUXV DQ LQFUHDVH LQ WKH SDUWLFOHWR3)8 UDWLR ,Q
505
DGGLWLRQDIRFXVH[SDQVLRQDVVD\)LJ FOHDUO\LQGLFDWHGWKDWWKHDEVHQFHRIS8/FDXVHVD
506
VHYHUH GHIHFW LQIRFDO VSUHDG :KLOH WKLV GHIHFW PD\ DOVREH UHODWHG WR D IXQFWLRQRIS8/
507
HDUO\LQLQIHFWLRQDQGORZHUDPRXQWVRIS8/LQYLULRQV)LJ LWFRXOGDOVREHUHODWHGWRD
508
IXQFWLRQODWHLQLQIHFWLRQDVUHSRUWHGIRUDOSKDKHUSHVYLUXVFRXQWHUSDUWS8/ ,Q
509
WKHFDVHRI3U9WKHS8/1WHUPLQXVLVLQYROYHGLQFHOOWRFHOOVSUHDGDQGVKDUHVVWUXFWXUDO
510
VLPLODULW\ZLWKFHOOXODUPXOWLVXEXQLWWHWKHULQJFRPSOH[HVZKLFKFRQWUROYHVLFXODUWUDIILFNLQJ
511
LQ HXNDU\RWLF FHOOV 7KLV VKRZV D VSHFLILF FHOOWRFHOO VSUHDG DVVRFLDWHG IXQFWLRQ RI
512
S8/ZKLFKFRXOGDOVRDSSO\WR+&09S8/JLYHQWKHKLJKFRQVHUYDWLRQRIWKLVSURWHLQ
513
DPRQJKHUSHVYLUXVHV+RZHYHUWKHH[DFWPHFKDQLVPVEHKLQGGLUHFWFHOOWRFHOOVSUHDGDUHQRW
20
514
HQWLUHO\ FOHDU DQG LW PD\ GLIIHU EHWZHHQ KHUSHVYLUXVHV FRQVLGHULQJ WKDW +&09 ODFNV WKH
515
DOSKDKHUSHVYLUXVVSUHDGUHODWHGJO\FRSURWHLQV(DQG,
516
:H DOVR REVHUYHG D UHGXFHG LQFRUSRUDWLRQ RI S8/ LQWR YLULRQV RI WKH 7%VWRS YLUXV
517
ZKLOH LQWUDFHOOXODU OHYHOV ZHUH XQDIIHFWHG )LJ :H FDQ RQO\ VSHFXODWH DERXW WKH UROH RI
518
S8/ IRU WKH LPSDLUHG JURZWK RI WKH 7%VWRS YLUXV EXW LW KDV WR EH PHQWLRQHG WKDW D
519
PXWDQW YLUXV XQDEOH WR H[SUHVV S8/ LV FKDUDFWHUL]HG E\D VPDOOSODTXH SKHQRW\SH DQG DQ
520
LPSDLUHGVHFRQGDU\HQYHORSPHQW 7KHUHIRUHDFRQWULEXWLRQRIS8/WRWKH7%VWRS
521
SKHQRW\SHKDVWREHDWOHDVWFRQVLGHUHG7KHILQGLQJWKDWLQWUDFHOOXODUOHYHOVRIS8/ZHUH
522
XQDIIHFWHG E\ WKH ODFN RI S8/ )LJ KLQWV WRZDUGV DQ LQWHUDFWLRQ ZLWK S8/ ZKLFK LV
523
LQWHUHVWLQJ EXW UHTXLUHV IXUWKHU LQYHVWLJDWLRQ 6R IDU WZR ODUJH