f7a7e8664f6839a315774b8fdb051c1d  322774.pdf
d635dbc4a619e17761f02fd9fc5339f061952a4b  322774.pdf
8d196ae0679fe06f5939d52663f33abe9077042a1c211bf9a6243cc79bc2e549  322774.pdf

Title:           Predictors of withdrawal of anticancer drug indications granted accelerated approval: a retrospective cohort study
Subject:         eClinicalMedicine, 84 (2025) 103088. doi:10.1016/j.eclinm.2025.103088
Author:          Ariadna Tibau
Creator:         Elsevier
Producer:        Acrobat Distiller 8.0.0 (Windows)
CreationDate:    Mon Jun 16 05:19:31 2025 CEST
ModDate:         Mon Jun 16 05:21:15 2025 CEST
Custom Metadata: yes
Metadata Stream: yes
Tagged:          no
UserProperties:  no
Suspects:        no
Form:            none
JavaScript:      no
Pages:           11
Encrypted:       no
Page size:       595.276 x 793.701 pts
Page rot:        0
File size:       563152 bytes
Optimized:       yes
PDF version:     1.7


name                                 type              encoding         emb sub uni object ID
------------------------------------ ----------------- ---------------- --- --- --- ---------
HFBANG+AdvOT20212610.B               Type 1C           WinAnsi          yes yes no     746  0
HFBANH+AdvOT2867105d.I               Type 1C           WinAnsi          yes yes no     749  0
HFBANI+AdvstixtSym                   Type 1C           Custom           yes yes yes    754  0
HFBAOI+AdvOT3f9da5b7                 Type 1C           WinAnsi          yes yes no     756  0
HFBAOJ+AdvOT3f9da5b7+20              Type 1C           WinAnsi          yes yes no     747  0
HFBAOK+AdvTT0d8bc80f.B               Type 1C           WinAnsi          yes yes no     763  0
HFBAOL+AdvTT0d8bc80f.B+fb            Type 1C           Custom           yes yes yes    768  0
HFBBAM+AdvTT0d8bc80f.B+20            Type 1C           WinAnsi          yes yes no     759  0
HFBBAN+AdvOTe3b1fbf3.B+22            Type 1C           Custom           yes yes yes    769  0
HFBBAO+AdvTTae869a4c                 Type 1C           WinAnsi          yes yes no     775  0
HFBBAP+AdvTTac2dc932                 Type 1C           WinAnsi          yes yes no     777  0
HFBBDO+AdvTTae869a4c+20              Type 1C           WinAnsi          yes yes no     441  0
HFBBEP+AdvTTae869a4c+fb              Type 1C           Custom           yes yes yes    442  0
HFBBFA+AdvOT3f9da5b7+fb              Type 1C           Custom           yes yes yes    443  0
HFBBIB+AdvTTb4077e6a                 Type 1C           WinAnsi          yes yes no     456  0
HFBBIC+AdvOT20212610.B+20            Type 1C           WinAnsi          yes yes no     457  0
HFBBHA+TimesNewRomanPSMT             CID TrueType      Identity-H       yes yes yes    458  0
HFBBJD+AdvOT20212610.B+fb            Type 1C           Custom           yes yes yes    470  0
HFBBLD+TimesNewRomanPS-BoldMT        CID TrueType      Identity-H       yes yes yes    481  0
HFBBLF+TimesNewRomanPS-BoldItalicMT  TrueType          WinAnsi          yes yes no     485  0
HFBCOO+Calibri                       CID TrueType      Identity-H       yes yes yes    492  0


Jhove (Rel. 1.28.0, 2023-05-18)
 Date: 2026-02-20 04:58:55 CET
 RepresentationInformation: 322774.pdf
  ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16)
  LastModified: 2026-02-19 09:02:23 CET
  Size: 563152
  Format: PDF
  Version: 1.7
  Status: Well-Formed, but not valid
  SignatureMatches:
   PDF-hul
  ErrorMessage: Invalid indirect destination - referenced object 'appsec1' cannot be found
   ID: PDF-HUL-149
  ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'appsec1' cannot be found
   ID: PDF-HUL-122
   Offset: 532870
  MIMEtype: application/pdf
  Profile: Linearized PDF
  PDFMetadata: 
   Objects: 841
   FreeObjects: 1
   IncrementalUpdates: 1
   DocumentCatalog: 
    PageLayout: SinglePage
    PageMode: UseOutlines
    Language: en
    Outlines: 
     Item: 
      Title: Predictors of withdrawal of anticancer drug indications granted accelerated approval: a retrospective cohort study
      Destination: titlink1
      Children: 
       Item: 
        Title: Introduction
        Destination: flink1
       Item: 
        Title: Methods
        Destination: flink2
        Children: 
         Item: 
          Title: Data sources
          Destination: slink1
         Item: 
          Title: Data extraction
          Destination: slink2
         Item: 
          Title: Data synthesis and scoring
          Destination: slink3
         Item: 
          Title: Statistical analysis
          Destination: slink4
         Item: 
          Title: Role of funding
          Destination: slink5
       Item: 
        Title: Results
        Destination: flink3
        Children: 
         Item: 
          Title: Indications for accelerated approval and characteristics of pivotal trials
          Destination: slink6
         Item: 
          Title: ESMO-MCBS thresholds
          Destination: slink7
         Item: 
          Title: Associations with verified benefit or withdrawal
          Destination: slink8
         Item: 
          Title: Temporal differences in associations
          Destination: slink9
       Item: 
        Title: Discussion
        Destination: flink4
       Item: 
        Title: ContributorsDrs Tibau and Romano had full access to all the data in the study and take responsibility for the integrity of  ...
        Destination: blink1
       Item: 
        Title: Data sharing statementThe datasets generated and analyzed during this study will be available from the corresponding author ...
        Destination: blink2
       Item: 
        Title: Declaration of interests
        Destination: blink3
       Item: 
        Title: Acknowledgements
        Destination: blink4
       Item: 
        Title: Appendix A. Supplementary data
        Destination: flink5
       Item: 
        Title: References
        Destination: blink5
   Info: 
    Title: Predictors of withdrawal of anticancer drug indications granted accelerated approval: a retrospective cohort study
    Author: Ariadna Tibau
    Subject: eClinicalMedicine, 84 (2025) 103088. doi:10.1016/j.eclinm.2025.103088
    Creator: Elsevier
    Producer: Acrobat Distiller 8.0.0 (Windows)
    CreationDate: Mon Jun 16 05:49:31 CEST 2025
    ModDate: Mon Jun 16 05:51:15 CEST 2025
   ID: 0x14d26f3fa8d7c227ec11f5b92eed707c, 0xc5160efe33b1a44b9ab1974e1bf1466c
   Filters: 
    FilterPipeline: FlateDecode
    FilterPipeline: DCTDecode
   Images: 
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 951
      ImageHeight: 1150
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
   Fonts: 
    Type0: 
     Font: 
      BaseFont: HFBBLD+TimesNewRomanPS-BoldMT
      Encoding: Identity-H
      ToUnicode: true
     Font: 
      BaseFont: HFBBHA+TimesNewRomanPSMT
      Encoding: Identity-H
      ToUnicode: true
     Font: 
      BaseFont: HFBCOO+Calibri
      Encoding: Identity-H
      ToUnicode: true
    Type1: 
     Font: 
      BaseFont: HFBAOL+AdvTT0d8bc80f.B+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 1
      FontDescriptor: 
       FontName: HFBAOL+AdvTT0d8bc80f.B+fb
       Flags: Symbolic
       FontBBox: 9, -10, 552, 729
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: HFBBAN+AdvOTe3b1fbf3.B+22
      FontSubset: true
      FirstChar: 1
      LastChar: 1
      FontDescriptor: 
       FontName: HFBBAN+AdvOTe3b1fbf3.B+22
       Flags: Symbolic
       FontBBox: 0, -406, 1343, 937
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: HFBBAO+AdvTTae869a4c
      FontSubset: true
      FirstChar: 37
      LastChar: 248
      FontDescriptor: 
       FontName: HFBBAO+AdvTTae869a4c
       Flags: Serif, Nonsymbolic
       FontBBox: 0, -250, 927, 864
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: HFBBIB+AdvTTb4077e6a
      FontSubset: true
      FirstChar: 46
      LastChar: 108
      FontDescriptor: 
       FontName: HFBBIB+AdvTTb4077e6a
       Flags: Nonsymbolic
       FontBBox: -104, -239, 822, 833
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: HFBBAP+AdvTTac2dc932
      FontSubset: true
      FirstChar: 45
      LastChar: 119
      FontDescriptor: 
       FontName: HFBBAP+AdvTTac2dc932
       Flags: Serif, Nonsymbolic
       FontBBox: -166, -250, 1010, 833
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: HFBBIC+AdvOT20212610.B+20
      FontSubset: true
      FirstChar: 150
      LastChar: 150
      FontDescriptor: 
       FontName: HFBBIC+AdvOT20212610.B+20
       Flags: Nonsymbolic
       FontBBox: -156, -187, 968, 739
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: HFBANG+AdvOT20212610.B
      FontSubset: true
      FirstChar: 37
      LastChar: 121
      FontDescriptor: 
       FontName: HFBANG+AdvOT20212610.B
       Flags: Nonsymbolic
       FontBBox: -52, -239, 833, 833
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: HFBAOJ+AdvOT3f9da5b7+20
      FontSubset: true
      FirstChar: 146
      LastChar: 151
      FontDescriptor: 
       FontName: HFBAOJ+AdvOT3f9da5b7+20
       Flags: Nonsymbolic
       FontBBox: -156, -177, 916, 739
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: HFBANH+AdvOT2867105d.I
      FontSubset: true
      FirstChar: 44
      LastChar: 119
      FontDescriptor: 
       FontName: HFBANH+AdvOT2867105d.I
       Flags: Serif, Nonsymbolic
       FontBBox: -104, -239, 791, 833
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: HFBANI+AdvstixtSym
      FontSubset: true
      FirstChar: 1
      LastChar: 1
      FontDescriptor: 
       FontName: HFBANI+AdvstixtSym
       Flags: Symbolic
       FontBBox: -20, -1114, 1135, 822
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: HFBAOI+AdvOT3f9da5b7
      FontSubset: true
      FirstChar: 37
      LastChar: 243
      FontDescriptor: 
       FontName: HFBAOI+AdvOT3f9da5b7
       Flags: Nonsymbolic
       FontBBox: -52, -239, 791, 833
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: HFBBJD+AdvOT20212610.B+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 1
      FontDescriptor: 
       FontName: HFBBJD+AdvOT20212610.B+fb
       Flags: Symbolic
       FontBBox: 0, 0, 781, 708
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: HFBBAM+AdvTT0d8bc80f.B+20
      FontSubset: true
      FirstChar: 150
      LastChar: 150
      FontDescriptor: 
       FontName: HFBBAM+AdvTT0d8bc80f.B+20
       Flags: Nonsymbolic
       FontBBox: -20, -239, 1197, 729
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: HFBBDO+AdvTTae869a4c+20
      FontSubset: true
      FirstChar: 145
      LastChar: 151
      FontDescriptor: 
       FontName: HFBBDO+AdvTTae869a4c+20
       Flags: Nonsymbolic
       FontBBox: -20, -239, 1197, 729
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: HFBBEP+AdvTTae869a4c+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 3
      FontDescriptor: 
       FontName: HFBBEP+AdvTTae869a4c+fb
       Flags: Symbolic
       FontBBox: 19, -10, 552, 729
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: HFBAOK+AdvTT0d8bc80f.B
      FontSubset: true
      FirstChar: 37
      LastChar: 237
      FontDescriptor: 
       FontName: HFBAOK+AdvTT0d8bc80f.B
       Flags: Serif, Nonsymbolic
       FontBBox: 0, -250, 947, 885
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: HFBBFA+AdvOT3f9da5b7+fb
      FontSubset: true
      FirstChar: 1
      LastChar: 3
      FontDescriptor: 
       FontName: HFBBFA+AdvOT3f9da5b7+fb
       Flags: Symbolic
       FontBBox: 0, 0, 697, 708
       FontFile3: true
      EncodingDictionary: 
       Differences: true
      ToUnicode: true
    TrueType: 
     Font: 
      BaseFont: HFBBLF+TimesNewRomanPS-BoldItalicMT
      FontSubset: true
      FirstChar: 80
      LastChar: 80
      FontDescriptor: 
       FontName: HFBBLF+TimesNewRomanPS-BoldItalicMT
       Flags: Serif, Nonsymbolic, Italic
       FontBBox: -547, -307, 1401, 1032
       FontFile2: true
      Encoding: WinAnsiEncoding
    CIDFontType2: 
     Font: 
      BaseFont: HFBBHA+TimesNewRomanPSMT
      CIDSystemInfo: 
       Registry: Adobe
       Registry: Identity
       Supplement: 0
      FontDescriptor: 
       FontName: HFBBHA+TimesNewRomanPSMT
       Flags: Serif, Symbolic
       FontBBox: -568, -307, 2046, 1040
       FontFile2: true
     Font: 
      BaseFont: HFBCOO+Calibri
      CIDSystemInfo: 
       Registry: Adobe
       Registry: Identity
       Supplement: 0
      FontDescriptor: 
       FontName: HFBCOO+Calibri
       Flags: Symbolic
       FontBBox: -503, -313, 1240, 1026
       FontFile2: true
     Font: 
      BaseFont: HFBBLD+TimesNewRomanPS-BoldMT
      CIDSystemInfo: 
       Registry: Adobe
       Registry: Identity
       Supplement: 0
      FontDescriptor: 
       FontName: HFBBLD+TimesNewRomanPS-BoldMT
       Flags: Serif, Symbolic
       FontBBox: -558, -328, 2000, 1056
       FontFile2: true
   XMP: <x:xmpmeta xmlns:x="adobe:ns:meta/" x:xmptk="Adobe XMP Core 4.0-c316 44.253921, Sun Oct 01 2006 17:14:39">
   <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about=""
            xmlns:dc="http://purl.org/dc/elements/1.1/">
         <dc:format>application/pdf</dc:format>
         <dc:identifier>doi:10.1016/j.eclinm.2025.103088</dc:identifier>
         <dc:title>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">Predictors of withdrawal of anticancer drug indications granted accelerated approval: a retrospective cohort study</rdf:li>
            </rdf:Alt>
         </dc:title>
         <dc:creator>
            <rdf:Seq>
               <rdf:li>Ariadna Tibau</rdf:li>
               <rdf:li>Edward R. Scheffer Cliff</rdf:li>
               <rdf:li>Alejandra Romano</rdf:li>
               <rdf:li>Maria Borrell</rdf:li>
               <rdf:li>Consolacion Molto</rdf:li>
               <rdf:li>Aaron S. Kesselheim</rdf:li>
            </rdf:Seq>
         </dc:creator>
         <dc:subject>
            <rdf:Bag>
               <rdf:li>Accelerated approval</rdf:li>
               <rdf:li>Drug withdrawal</rdf:li>
               <rdf:li>Food and drug administration (FDA)</rdf:li>
               <rdf:li>European Society of Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS)</rdf:li>
               <rdf:li>Cancer therapy</rdf:li>
            </rdf:Bag>
         </dc:subject>
         <dc:description>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">eClinicalMedicine, 84 (2025) 103088. doi:10.1016/j.eclinm.2025.103088</rdf:li>
            </rdf:Alt>
         </dc:description>
         <dc:publisher>
            <rdf:Bag>
               <rdf:li>The Authors</rdf:li>
            </rdf:Bag>
         </dc:publisher>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:prism="http://prismstandard.org/namespaces/basic/3.0/">
         <prism:aggregationType>journal</prism:aggregationType>
         <prism:publicationName>eClinicalMedicine</prism:publicationName>
         <prism:copyright>© 2025 The Authors. Published by Elsevier Ltd.</prism:copyright>
         <prism:issn>2589-5370</prism:issn>
         <prism:volume>84</prism:volume>
         <prism:coverDisplayDate>June 2025</prism:coverDisplayDate>
         <prism:pageRange>103088</prism:pageRange>
         <prism:startingPage>103088</prism:startingPage>
         <prism:doi>10.1016/j.eclinm.2025.103088</prism:doi>
         <prism:url>https://doi.org/10.1016/j.eclinm.2025.103088</prism:url>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:crossmark="http://crossref.org/crossmark/1.0/">
         <crossmark:MajorVersionDate>2010-04-23</crossmark:MajorVersionDate>
         <crossmark:CrossmarkDomainExclusive>true</crossmark:CrossmarkDomainExclusive>
         <crossmark:DOI>10.1016/j.eclinm.2025.103088</crossmark:DOI>
         <crossmark:CrossMarkDomains>
            <rdf:Seq>
               <rdf:li>elsevier.com</rdf:li>
               <rdf:li>sciencedirect.com</rdf:li>
            </rdf:Seq>
         </crossmark:CrossMarkDomains>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:jav="http://www.niso.org/schemas/jav/1.0/">
         <jav:journal_article_version>VoR</jav:journal_article_version>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:pdfx="http://ns.adobe.com/pdfx/1.3/">
         <pdfx:ElsevierWebPDFSpecifications>7.0.1</pdfx:ElsevierWebPDFSpecifications>
         <pdfx:doi>10.1016/j.eclinm.2025.103088</pdfx:doi>
         <pdfx:robots>noindex</pdfx:robots>
         <pdfx:CrossmarkMajorVersionDate>2010-04-23</pdfx:CrossmarkMajorVersionDate>
         <pdfx:CrossmarkDomainExclusive>true</pdfx:CrossmarkDomainExclusive>
         <pdfx:CrossMarkDomains>
            <rdf:Seq>
               <rdf:li>sciencedirect.com</rdf:li>
               <rdf:li>elsevier.com</rdf:li>
            </rdf:Seq>
         </pdfx:CrossMarkDomains>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:xap="http://ns.adobe.com/xap/1.0/">
         <xap:CreatorTool>Elsevier</xap:CreatorTool>
         <xap:CreateDate>2025-06-16T08:49:31+05:30</xap:CreateDate>
         <xap:ModifyDate>2025-06-16T08:51:15+05:30</xap:ModifyDate>
         <xap:MetadataDate>2025-06-16T08:51:15+05:30</xap:MetadataDate>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:xapRights="http://ns.adobe.com/xap/1.0/rights/">
         <xapRights:Marked>True</xapRights:Marked>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:tdm="http://www.w3.org/ns/tdmrep/">
         <tdm:reservation>1</tdm:reservation>
         <tdm:policy>https://www.elsevier.com/tdm/tdmrep-policy.json</tdm:policy>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:pdf="http://ns.adobe.com/pdf/1.3/">
         <pdf:Producer>Acrobat Distiller 8.0.0 (Windows)</pdf:Producer>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:xapMM="http://ns.adobe.com/xap/1.0/mm/">
         <xapMM:DocumentID>uuid:c6634fe4-c00e-4af4-bdd9-6e04c369472e</xapMM:DocumentID>
         <xapMM:InstanceID>uuid:85398427-2a0e-47fd-8ed6-3a9a2fab2b29</xapMM:InstanceID>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:ali="http://www.niso.org/schemas/ali/1.0/">
         <ali:license_ref>
            <rdf:Bag>
               <rdf:li rdf:parseType="Resource">
                  <ali:uri>http://creativecommons.org/licenses/by/4.0/</ali:uri>
               </rdf:li>
            </rdf:Bag>
         </ali:license_ref>
      </rdf:Description>
   </rdf:RDF>
</x:xmpmeta>
   Pages: 
    Page: 
     Label: 1
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 81, 610, 81, 612
      Annotation: 
       Subtype: Link
       Rect: 83, 611, 86, 617
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 87, 611, 90, 619
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 91, 611, 93, 617
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 94, 611, 97, 619
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 98, 611, 102, 617
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 173, 610, 173, 612
      Annotation: 
       Subtype: Link
       Rect: 175, 611, 178, 617
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 179, 611, 182, 619
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 183, 611, 186, 617
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 186, 611, 189, 619
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 246, 610, 246, 612
      Annotation: 
       Subtype: Link
       Rect: 248, 611, 251, 617
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 251, 611, 255, 619
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 295, 610, 295, 612
      Annotation: 
       Subtype: Link
       Rect: 296, 611, 300, 617
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 300, 611, 304, 619
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 361, 610, 361, 612
      Annotation: 
       Subtype: Link
       Rect: 363, 611, 364, 618
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 365, 611, 367, 618
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 368, 611, 371, 619
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 446, 610, 446, 612
      Annotation: 
       Subtype: Link
       Rect: 446, 611, 449, 617
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 450, 611, 453, 619
       Destination: 679
      Annotation: 
       Subtype: Link
       Rect: 42, 98, 211, 107
      Annotation: 
       Subtype: Link
       Rect: 100, 43, 201, 50
      Annotation: 
       Subtype: Link
       Rect: 205, 43, 263, 50
      Annotation: 
       Subtype: Link
       Rect: 487, 639, 515, 667
      Annotation: 
       Subtype: Link
       Rect: 487, 412, 540, 420
      Annotation: 
       Subtype: Link
       Rect: 487, 402, 544, 410
      Annotation: 
       Subtype: Link
       Rect: 487, 393, 510, 400
      Annotation: 
       Subtype: Link
       Rect: 39, 12, 96, 19
    Page: 
     Label: 2
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 256, 105, 258, 112
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 258, 105, 258, 114
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 203, 83, 206, 90
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 206, 83, 206, 92
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 184, 72, 187, 79
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 187, 72, 187, 81
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 326, 72, 328, 79
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 415, 236, 417, 243
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 417, 237, 417, 246
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 397, 225, 399, 232
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 399, 226, 399, 235
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 509, 214, 511, 221
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 511, 215, 511, 224
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 490, 160, 493, 166
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 524, 105, 526, 112
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 527, 105, 533, 112
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 363, 83, 368, 90
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 388, 72, 393, 79
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 471, 61, 476, 68
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 444, 12, 501, 19
    Page: 
     Label: 3
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 161, 476, 166, 483
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 244, 454, 249, 461
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 163, 443, 168, 450
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 110, 388, 115, 395
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 116, 388, 122, 395
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 56, 377, 61, 384
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 202, 377, 207, 384
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 132, 114, 137, 121
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 183, 92, 188, 99
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 102, 67, 167, 76
      Annotation: 
       Subtype: Link
       Rect: 375, 662, 380, 669
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 300, 640, 305, 647
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 357, 575, 362, 581
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 450, 542, 455, 549
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 297, 520, 302, 527
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 284, 498, 289, 505
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 346, 487, 351, 494
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 369, 465, 374, 472
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 332, 443, 337, 450
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 340, 440, 433, 449
       Destination: null
      Annotation: 
       Subtype: Link
       Rect: 39, 12, 96, 19
    Page: 
     Label: 4
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 271, 352, 328, 361
       Destination: null
      Annotation: 
       Subtype: Link
       Rect: 118, 341, 160, 350
       Destination: null
      Annotation: 
       Subtype: Link
       Rect: 121, 330, 222, 339
       Destination: null
      Annotation: 
       Subtype: Link
       Rect: 481, 637, 502, 646
       Destination: 53
      Annotation: 
       Subtype: Link
       Rect: 401, 494, 429, 503
       Destination: 69
      Annotation: 
       Subtype: Link
       Rect: 444, 12, 501, 19
    Page: 
     Label: 5
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 266, 231, 357, 240
       Destination: null
      Annotation: 
       Subtype: Link
       Rect: 266, 56, 288, 65
       Destination: 80
      Annotation: 
       Subtype: Link
       Rect: 143, 485, 145, 492
       Destination: 69
      Annotation: 
       Subtype: Link
       Rect: 70, 131, 73, 138
       Destination: 69
      Annotation: 
       Subtype: Link
       Rect: 309, 570, 311, 577
       Destination: 69
      Annotation: 
       Subtype: Link
       Rect: 39, 12, 96, 19
    Page: 
     Label: 6
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 348, 248, 441, 257
       Destination: null
      Annotation: 
       Subtype: Link
       Rect: 348, 94, 377, 103
       Destination: 96
      Annotation: 
       Subtype: Link
       Rect: 444, 12, 501, 19
    Page: 
     Label: 7
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 300, 343, 305, 350
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 427, 200, 433, 207
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 282, 178, 287, 185
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 457, 146, 462, 152
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 463, 146, 468, 152
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 471, 80, 476, 87
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 300, 644, 302, 651
       Destination: 96
      Annotation: 
       Subtype: Link
       Rect: 380, 644, 383, 651
       Destination: 96
      Annotation: 
       Subtype: Link
       Rect: 456, 644, 459, 651
       Destination: 96
      Annotation: 
       Subtype: Link
       Rect: 168, 599, 170, 606
       Destination: 96
      Annotation: 
       Subtype: Link
       Rect: 227, 588, 230, 595
       Destination: 96
      Annotation: 
       Subtype: Link
       Rect: 234, 557, 236, 564
       Destination: 96
      Annotation: 
       Subtype: Link
       Rect: 111, 515, 113, 522
       Destination: 96
      Annotation: 
       Subtype: Link
       Rect: 233, 494, 235, 501
       Destination: 96
      Annotation: 
       Subtype: Link
       Rect: 67, 388, 70, 395
       Destination: 96
      Annotation: 
       Subtype: Link
       Rect: 39, 12, 96, 19
    Page: 
     Label: 8
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 295, 169, 300, 176
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 184, 114, 189, 121
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 282, 49, 287, 55
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 413, 608, 418, 614
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 517, 553, 522, 559
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 375, 410, 380, 417
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 375, 377, 380, 384
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 550, 377, 555, 384
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 489, 202, 494, 209
       Destination: 384
      Annotation: 
       Subtype: Link
       Rect: 495, 202, 500, 209
       Destination: 384
      Annotation: 
       Subtype: Link
       Rect: 444, 12, 501, 19
    Page: 
     Label: 9
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 106, 454, 111, 461
       Destination: 384
      Annotation: 
       Subtype: Link
       Rect: 111, 455, 111, 464
       Destination: 384
      Annotation: 
       Subtype: Link
       Rect: 84, 410, 89, 417
       Destination: 384
      Annotation: 
       Subtype: Link
       Rect: 89, 411, 89, 420
       Destination: 384
      Annotation: 
       Subtype: Link
       Rect: 188, 355, 192, 362
       Destination: 384
      Annotation: 
       Subtype: Link
       Rect: 192, 356, 193, 365
       Destination: 384
      Annotation: 
       Subtype: Link
       Rect: 165, 334, 170, 340
       Destination: 384
      Annotation: 
       Subtype: Link
       Rect: 171, 334, 176, 340
       Destination: 384
      Annotation: 
       Subtype: Link
       Rect: 161, 268, 166, 275
       Destination: 384
      Annotation: 
       Subtype: Link
       Rect: 186, 235, 188, 242
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 189, 235, 195, 242
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 185, 147, 190, 154
       Destination: 384
      Annotation: 
       Subtype: Link
       Rect: 471, 520, 476, 527
       Destination: 152
      Annotation: 
       Subtype: Link
       Rect: 39, 12, 96, 19
    Page: 
     Label: 10
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 295, 524, 328, 531
      Annotation: 
       Subtype: Link
       Rect: 118, 515, 219, 522
      Annotation: 
       Subtype: Link
       Rect: 132, 477, 328, 484
      Annotation: 
       Subtype: Link
       Rect: 132, 469, 328, 476
      Annotation: 
       Subtype: Link
       Rect: 132, 462, 328, 469
      Annotation: 
       Subtype: Link
       Rect: 132, 454, 198, 461
      Annotation: 
       Subtype: Link
       Rect: 132, 446, 328, 453
      Annotation: 
       Subtype: Link
       Rect: 132, 438, 328, 445
      Annotation: 
       Subtype: Link
       Rect: 132, 430, 185, 437
      Annotation: 
       Subtype: Link
       Rect: 132, 422, 328, 429
      Annotation: 
       Subtype: Link
       Rect: 132, 414, 328, 421
      Annotation: 
       Subtype: Link
       Rect: 132, 406, 328, 413
      Annotation: 
       Subtype: Link
       Rect: 132, 398, 255, 405
      Annotation: 
       Subtype: Link
       Rect: 132, 390, 328, 397
      Annotation: 
       Subtype: Link
       Rect: 132, 382, 326, 389
      Annotation: 
       Subtype: Link
       Rect: 132, 374, 328, 381
      Annotation: 
       Subtype: Link
       Rect: 132, 366, 328, 373
      Annotation: 
       Subtype: Link
       Rect: 132, 358, 174, 365
      Annotation: 
       Subtype: Link
       Rect: 132, 350, 328, 357
      Annotation: 
       Subtype: Link
       Rect: 132, 342, 328, 349
      Annotation: 
       Subtype: Link
       Rect: 132, 334, 328, 341
      Annotation: 
       Subtype: Link
       Rect: 132, 326, 171, 333
      Annotation: 
       Subtype: Link
       Rect: 132, 318, 328, 325
      Annotation: 
       Subtype: Link
       Rect: 132, 310, 328, 317
      Annotation: 
       Subtype: Link
       Rect: 132, 302, 281, 309
      Annotation: 
       Subtype: Link
       Rect: 132, 294, 328, 301
      Annotation: 
       Subtype: Link
       Rect: 132, 286, 328, 293
      Annotation: 
       Subtype: Link
       Rect: 132, 278, 328, 285
      Annotation: 
       Subtype: Link
       Rect: 132, 270, 188, 277
      Annotation: 
       Subtype: Link
       Rect: 132, 262, 328, 269
      Annotation: 
       Subtype: Link
       Rect: 132, 254, 328, 261
      Annotation: 
       Subtype: Link
       Rect: 132, 246, 313, 253
      Annotation: 
       Subtype: Link
       Rect: 132, 238, 328, 245
      Annotation: 
       Subtype: Link
       Rect: 132, 230, 328, 237
      Annotation: 
       Subtype: Link
       Rect: 132, 222, 328, 229
      Annotation: 
       Subtype: Link
       Rect: 132, 214, 188, 221
      Annotation: 
       Subtype: Link
       Rect: 180, 198, 328, 205
      Annotation: 
       Subtype: Link
       Rect: 132, 191, 289, 198
      Annotation: 
       Subtype: Link
       Rect: 247, 167, 328, 174
      Annotation: 
       Subtype: Link
       Rect: 132, 159, 328, 166
      Annotation: 
       Subtype: Link
       Rect: 132, 151, 191, 158
      Annotation: 
       Subtype: Link
       Rect: 217, 135, 328, 142
      Annotation: 
       Subtype: Link
       Rect: 132, 127, 326, 134
      Annotation: 
       Subtype: Link
       Rect: 180, 103, 328, 110
      Annotation: 
       Subtype: Link
       Rect: 132, 95, 328, 102
      Annotation: 
       Subtype: Link
       Rect: 132, 87, 167, 94
      Annotation: 
       Subtype: Link
       Rect: 218, 71, 328, 78
      Annotation: 
       Subtype: Link
       Rect: 132, 63, 243, 70
      Annotation: 
       Subtype: Link
       Rect: 234, 47, 328, 54
      Annotation: 
       Subtype: Link
       Rect: 359, 661, 500, 668
      Annotation: 
       Subtype: Link
       Rect: 407, 637, 555, 644
      Annotation: 
       Subtype: Link
       Rect: 359, 629, 539, 636
      Annotation: 
       Subtype: Link
       Rect: 359, 605, 550, 612
      Annotation: 
       Subtype: Link
       Rect: 359, 589, 555, 596
      Annotation: 
       Subtype: Link
       Rect: 359, 581, 555, 588
      Annotation: 
       Subtype: Link
       Rect: 359, 573, 487, 580
      Annotation: 
       Subtype: Link
       Rect: 359, 565, 555, 572
      Annotation: 
       Subtype: Link
       Rect: 359, 557, 542, 564
      Annotation: 
       Subtype: Link
       Rect: 359, 549, 555, 556
      Annotation: 
       Subtype: Link
       Rect: 359, 541, 555, 548
      Annotation: 
       Subtype: Link
       Rect: 359, 533, 419, 540
      Annotation: 
       Subtype: Link
       Rect: 359, 509, 554, 516
      Annotation: 
       Subtype: Link
       Rect: 359, 501, 365, 508
      Annotation: 
       Subtype: Link
       Rect: 359, 485, 499, 492
      Annotation: 
       Subtype: Link
       Rect: 359, 469, 555, 476
      Annotation: 
       Subtype: Link
       Rect: 359, 461, 525, 468
      Annotation: 
       Subtype: Link
       Rect: 359, 453, 555, 460
      Annotation: 
       Subtype: Link
       Rect: 359, 445, 555, 452
      Annotation: 
       Subtype: Link
       Rect: 359, 437, 510, 444
      Annotation: 
       Subtype: Link
       Rect: 359, 414, 552, 421
      Annotation: 
       Subtype: Link
       Rect: 359, 406, 475, 413
      Annotation: 
       Subtype: Link
       Rect: 359, 390, 555, 397
      Annotation: 
       Subtype: Link
       Rect: 359, 382, 555, 389
      Annotation: 
       Subtype: Link
       Rect: 359, 374, 408, 381
      Annotation: 
       Subtype: Link
       Rect: 392, 350, 555, 357
      Annotation: 
       Subtype: Link
       Rect: 359, 342, 554, 349
      Annotation: 
       Subtype: Link
       Rect: 359, 334, 446, 341
      Annotation: 
       Subtype: Link
       Rect: 359, 326, 555, 333
      Annotation: 
       Subtype: Link
       Rect: 359, 318, 398, 325
      Annotation: 
       Subtype: Link
       Rect: 359, 310, 555, 317
      Annotation: 
       Subtype: Link
       Rect: 359, 302, 555, 309
      Annotation: 
       Subtype: Link
       Rect: 359, 294, 555, 301
      Annotation: 
       Subtype: Link
       Rect: 359, 286, 415, 293
      Annotation: 
       Subtype: Link
       Rect: 359, 278, 555, 285
      Annotation: 
       Subtype: Link
       Rect: 359, 270, 555, 277
      Annotation: 
       Subtype: Link
       Rect: 359, 262, 555, 269
      Annotation: 
       Subtype: Link
       Rect: 359, 254, 391, 261
      Annotation: 
       Subtype: Link
       Rect: 359, 246, 555, 253
      Annotation: 
       Subtype: Link
       Rect: 359, 238, 555, 245
      Annotation: 
       Subtype: Link
       Rect: 359, 230, 443, 237
      Annotation: 
       Subtype: Link
       Rect: 359, 222, 555, 229
      Annotation: 
       Subtype: Link
       Rect: 359, 214, 555, 221
      Annotation: 
       Subtype: Link
       Rect: 359, 206, 419, 213
      Annotation: 
       Subtype: Link
       Rect: 359, 198, 555, 205
      Annotation: 
       Subtype: Link
       Rect: 359, 190, 523, 197
      Annotation: 
       Subtype: Link
       Rect: 359, 182, 555, 189
      Annotation: 
       Subtype: Link
       Rect: 359, 174, 555, 181
      Annotation: 
       Subtype: Link
       Rect: 359, 166, 555, 173
      Annotation: 
       Subtype: Link
       Rect: 359, 159, 394, 165
      Annotation: 
       Subtype: Link
       Rect: 359, 151, 555, 158
      Annotation: 
       Subtype: Link
       Rect: 359, 143, 555, 150
      Annotation: 
       Subtype: Link
       Rect: 359, 135, 555, 142
      Annotation: 
       Subtype: Link
       Rect: 359, 127, 555, 134
      Annotation: 
       Subtype: Link
       Rect: 359, 119, 552, 126
      Annotation: 
       Subtype: Link
       Rect: 359, 111, 555, 118
      Annotation: 
       Subtype: Link
       Rect: 359, 103, 555, 110
      Annotation: 
       Subtype: Link
       Rect: 359, 95, 524, 102
      Annotation: 
       Subtype: Link
       Rect: 359, 87, 555, 94
      Annotation: 
       Subtype: Link
       Rect: 359, 79, 555, 86
      Annotation: 
       Subtype: Link
       Rect: 359, 71, 545, 78
      Annotation: 
       Subtype: Link
       Rect: 359, 63, 555, 70
      Annotation: 
       Subtype: Link
       Rect: 359, 55, 555, 62
      Annotation: 
       Subtype: Link
       Rect: 359, 47, 455, 54
      Annotation: 
       Subtype: Link
       Rect: 444, 12, 501, 19
    Page: 
     Label: 11
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 53, 661, 249, 668
      Annotation: 
       Subtype: Link
       Rect: 53, 653, 249, 660
      Annotation: 
       Subtype: Link
       Rect: 53, 645, 249, 652
      Annotation: 
       Subtype: Link
       Rect: 53, 637, 125, 644
      Annotation: 
       Subtype: Link
       Rect: 53, 629, 249, 636
      Annotation: 
       Subtype: Link
       Rect: 53, 621, 249, 628
      Annotation: 
       Subtype: Link
       Rect: 53, 613, 185, 620
      Annotation: 
       Subtype: Link
       Rect: 53, 605, 249, 612
      Annotation: 
       Subtype: Link
       Rect: 53, 597, 249, 604
      Annotation: 
       Subtype: Link
       Rect: 53, 589, 122, 596
      Annotation: 
       Subtype: Link
       Rect: 53, 581, 249, 588
      Annotation: 
       Subtype: Link
       Rect: 53, 573, 219, 580
      Annotation: 
       Subtype: Link
       Rect: 280, 661, 476, 668
      Annotation: 
       Subtype: Link
       Rect: 280, 653, 476, 660
      Annotation: 
       Subtype: Link
       Rect: 280, 645, 449, 652
      Annotation: 
       Subtype: Link
       Rect: 280, 637, 476, 644
      Annotation: 
       Subtype: Link
       Rect: 280, 629, 476, 636
      Annotation: 
       Subtype: Link
       Rect: 280, 621, 474, 628
      Annotation: 
       Subtype: Link
       Rect: 280, 613, 476, 620
      Annotation: 
       Subtype: Link
       Rect: 280, 605, 476, 612
      Annotation: 
       Subtype: Link
       Rect: 280, 597, 474, 604
      Annotation: 
       Subtype: Link
       Rect: 280, 589, 476, 596
      Annotation: 
       Subtype: Link
       Rect: 280, 581, 476, 588
      Annotation: 
       Subtype: Link
       Rect: 280, 573, 329, 580
      Annotation: 
       Subtype: Link
       Rect: 39, 12, 96, 19
  Checksum: 021432a5
   Type: CRC32
  Checksum: f7a7e8664f6839a315774b8fdb051c1d
   Type: MD5
  Checksum: d635dbc4a619e17761f02fd9fc5339f061952a4b
   Type: SHA-1
  Checksum: 8d196ae0679fe06f5939d52663f33abe9077042a1c211bf9a6243cc79bc2e549
   Type: SHA-256