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HD Innovators Forum Thursday, November 3 4:45-4:45pm Moderators: Blair Leavitt and Christopher Ross HSG Scientific Advisory Committee Chairs

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HD Innovators ForumThursday, November 34:45-4:45pmModerators: Blair Leavitt and Christopher RossHSG Scientific Advisory Committee Chairs

PresentersHSG 2016: Discovering Our FutureMike Panzara, MD, MPHWAVE Life Sciences

Pavlina Konstantnova, PhDuniQure

Anne Smith, PhDIonis Pharmaceuticals

Use of optimized stereochemistry to target the Huntingtons Disease allele mRNA by antisense oligonucleotide treatmentMichael A. Panzara, MD, MPHHead of Neurology Franchise, WAVE Life SciencesNovember 3, 2016

FoundedOntorii (USA)Chemistry & PharmacologyChiralgen (Japan)Manufacturing

20092013MergerWAVE Life Sciences2015Financings2 private rounds~$196M CashLicenseTuschl ssRNAi IPO (WVE)2016Two IND filings expected for Huntingtons disease lead programs (WVE-120101, WVE-120102) YE 2016Clinical Trials expected to commence 2017 for 2 lead Huntingtons disease programs2017IND filing and initiation of clinical trial for lead program in Duchenne Muscular Dystrophy in 2017Targeting 6 IND filings by end of 201820+ programs in early discovery and pre-clinical developmentStrategic partnerships complementinternal neurology focus areas (ex. Pfizer May 2016)Cash runway into 20192018+Pipeline GrowthGalNAc POC2 INDs expected YE 20166 INDSubmissions by 2018

Manufacturing Capabilities Expanded Foundation of Intellectual Property

CollaborationMetabolic diseaseHepatic targeting technology2017: ClinicalPlatform Expansion & Pipeline DevelopmentWAVE Life Sciences

A Genetic Medicines CompanyDeveloping targeted therapies for patients impacted by rare diseasesClinical DevelopmentInitiate 3 clinical trials 20172 additional INDs YE 2017

BACKGROUND3

Phosphorothioate (PS) backbone modification introduced into nucleic acid based therapies:Provides good stability and bio-availabilityAdopts random three-dimensional arrangements during synthesisResults in exponentially diverse drug mixtures with 2N stereoisomers (N = number of PS)Drug mixtures may suffer from efficacy, safety and distribution issues19 phosphorothioate (PS) linkers1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Each PS linker

=OR=219Mipomersen (219 = 524,288)

Stereo-randomRp-stereoisomerSp-stereoisomerDrug mixture

PhosphodiesterPhosphorothioateSpRp

WAVE proprietary platform precisely controls oligonucleotide stereochemistry

Enables control of pharmacology and rational drug design with potential to improve stability, activity, stability, immunogenicity and specificity

Scalable synthesis

Applicable to any nucleic acid based therapy and targeting moieties

Unique ability to optimize pharmacology across the therapeutic classPLATFORM4Mixtures

RpSp

NucleotideLinkerWAVE Chemical ControlWAVE Optimized Isomers

StabilityActivityImmuneSpecificity

WAVE Design

AntisenseRNAiExon skipping

Optimized isomers

WAVE PipelineKey: Est 2017Clinical TrialI: Anticipated IND filingsC: Candidate Nomination Estimated inflection point for candidate selection effortsThis chart contains forward-looking statements.

Core Neurology Portfolio

(2)

Two lead programs in HD, IND filings expected in 2016The DiseaseAutosomal dominant disorder, involving the HTT gene, characterized by chorea, psychiatric illness and cognitive declineApproximately 30,000 individuals have symptomatic HD in the United StatesNo approved disease-modifying therapies availableWAVE ApproachSelective reduction of mutant HTT while leaving wild-type HTT intact could be disease modifyingTargeting single nucleotide polymorphisms (SNPs) associated with causative mutations provides an approach to allele-specific gene silencingOver two-thirds of patients are eligible to use WAVEs first two programs due to prevalence of SNPs associated with the mutant alleles

Huntington (HTT)Wild-type (healthy) alleleMutant allele

SNPCAG repeatDisease causing mutations

SNP associated with CAG repeatEnables targets for allele-specific silencing

100%

75%25%0%

Number of SNPs targetedHD Patients coveredCumulative HD Patient Coverage

50%Huntingtons Disease (HD)~77%~80%~71%~55%1234

WVE-120101 Selectively Cleaves mHTT RNANo Complement Immune System Response

WVE-120101 Selectively Reduces mHTT mRNA and Protein

Distribution of WVE-120101 in Cynomolgus NHP Brain

Animal # 42, Slice 8Red dots are WVE-120101. Arrow points to nuclear and perinuclear distribution of WVE-120101 in cingulate cortexIn Situ Hybridization ViewRNA stained tissueWVE-120101 detectable in deep gray matter structures following intrathecal administration

Distribution of WVE-120101 in Cynomolgus NHP BrainWVE-120101 detectable in deep gray matter structures following intrathecal administrationAnimal # 42, slice 8

D

Red dots are WVE-120101. Arrow points to nuclear and perinuclear distribution of WVE-120101 in caudate nucleus

Two concurrent global Phase 1b/2a placebo-controlled studies targeting SNP1 and SNP2Primary Objective: Assess safety and tolerability of single ascending and multiple intrathecal doses in early manifest HD patientsExploratory pharmacokinetic, pharmacodynamic, clinical and MRI endpointsSNP determination at initial screening visitKey inclusion criteriaAge 25 to 65Stage I or Stage II Huntingtons disease

INDs expected to file by YE 2016WVE-120101 and WVE-120102 Clinical Development

Patient Selection for WVE-120101/2 Clinical StudiesPatients with the targeted SNP on the same allele as the pathogenic CAG expansion will be eligible

Control of oligonucleotide stereochemistry enables rational drug design and control of pharmacology of nucleic acid therapeuticsPotential to improve stability, activity, stability, immunogenicity and specificity

Scalable synthesis

Application to any nucleic acid based therapy and targeting moietiesIn HD, WVE-120101 selectively decreased mHTT mRNA and protein levels compared with wtHTT in multiple cell lines with SNP1 allele with good brain distributionTargeting SNP1 and SNP2 may provide the possibility of treating over two-thirds of the total HD patient populationThe ability to selectively reduce mHTT protein, while retaining healthy HTT protein, might provide disease-modifying effects in HDConclusions

Refining experimental gene therapies for Huntingtons and other diseasesPavlina KonstantinovaDirector Emerging Technologies24th of February 2016, CHDI meeting

Development of HTT lowering gene therapy using AAV vectorsPavlina Konstantinova, PhDDirector Emerging Technologies

This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words anticipate, believe, estimate, expect, intend, may, plan, predict, project, target, potential, will, would, could, should, continue, and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. The forward-looking statements contained in this presentation reflect uniQures current views with respect to future events, and uniQure assumes no obligation to update any forward-looking statements except as required by applicable law.FORWARD-LOOKING STATEMENTS

Idea of Gene Therapy is Simple18Replace in a one-time administration a gene that does not function with a functioning gene to fix what is causing disease

GeneTherapeutic correction

VectorDelivery vehicle

ManufacturingGene / vector copies

AdministrationTarget tissue

MFG scale based on number of patients Scale up possible (LEX).18

natural AAV DIRECTED EVOLUTION optimized AAV

Natural AAV Variants and Target Tissue Tailored VectorsTROPISM

AAV1 Exclusivity for LPLDAAV2AAV5 Exclusivity for LIVER and CNSAAV6AAV8AAV9

Synthetic AAV Mutants

Synthetic AAV Mutants

Synthetic AAV Mutants

Synthetic AAV Mutants

Synthetic AAV Mutants

Synthetic AAV Mutants

Synthetic AAV Mutants

Synthetic AAV Mutants

Synthetic AAV Mutants

Synthetic AAV Mutants

Synthetic AAV Super Mutants4D Therapeutics

#Confidential

AAV5 uniQures Proprietary and Proven Vector Validated delivery technology20 patients successfully treatedLowest prevalence of pre-existing antibodies amongst natural AAV serotypesSuccessful delivery in liver and brain tissuesPotential for a wide variety of indications across multiple therapeutic areas Initial efficacy established in Hemophilia B and Sanfilippo B Proven safety in three clinical trials

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AAV5

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211Pringsheim et al. Mov. Disord. (2012)

Worldwide prevalence of 2.71 in 100,0001; EU/US 5.70 in 100,0001No treatment availablePublished proof of concept of therapeutically relevant knock-down in humanized mouse/rate modelsLead selection completedNon-clinical safety toxicology studies ongoingInitiate first-in-man study

Market

Status

Data to Date

Next StepsHuntington's Disease Program OverviewTarget indication - Reduction of mutant aggregating huntingtin to decrease toxic burden

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Product development for AAV5 HD gene therapyAge/yearsSymptom severity1020304050607080

Disease onset and diagnosis

Single treatmentAAV5-miRNA gene therapySlow down disease progressionTreatment after disease onsetSlow down of disease progressionPre-symptomatic phaseSymptomatic phase

#

Companies developing HTT lowering therapies (both alleles are targeted) IONIS Pharmaceuticals started Phase I/IIa trial in July 2015 with ASO targeting HTT

Voyager/Genzyme develop AAV1-miRNA targeting HTT (to be in GLP-Tox in 2017)

Spark is proceeding with AAV1-miRNA targeting HTT (to be in GLP-Tox in 2016)

#

AAV5-miHTT gene therapy for HDTherapeutic RNA interference

binding to cell surfaceheparan sulphate proteoglycan

internalization

vesicle escape and transport to nucleus

Uncoating and miRNA expressionAAV vector

cytoplasm

nucleus

AAA

Target cell(neurons)

Huntingtin mRNAbinding

Huntingtindegradation

#

At uniQure we are aiming at permanent RNAi gene therapy approach for HD. The idea is that the AAV vector, carrying artificial miRNA or a transgene, will be injected once in brain and that will result in a long-term expression of the effector molecule. RNAi companies like IONIS, Santaris, Alnylam, Silence, Tekmira and Merk, use synthetically synthesized siRNA to induce RNAi. The disadvantages of this approach are that siRNA need to be injected weekly or bi-monthly, which is not desirable in HD therapy. Another disadvantage is siRNA toxicity due to accumulation of those molecules in different organs.

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AAV5-miHTT targeting HTT exon 1

Wild type HTT geneMutant HTT gene

CAG tract

Expanded CAG tract

Silencing of both wild-type (wt) and mutant (mt) HTT allelesIn HD rodent models 75% knock-down of HTT is therapeutic (Drouet et al. 2009, Boudreau et al. 2009, Stiles et al. 2012)In NHPs 50% knock-down of HTT is well tolerated (Kordasiewicz et al. 2012, McBride et al. 2012)

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The miHTT therapeutic lead selection processTherapeutic candidate selectionIn vitro selectionmiRNA scaffold optimization incorporate best miHTT in different cellular scaffoldsIn vivo efficacy in HD mice transduction, HTT silencing, phenotype improvementSafety ongoingMiniarikova et al. MolTher NA, 2016

CAG promoterpolyAmiHTT-451

~2.8 kb5ITR3ITRCAG, chicken beta actin promoter; ITR, inverted terminal repeats

Broad brain distribution of AAV5-GFP-miHTT in miceAmber Southwell, UBC 27

Forebrain, striatum, cortex, and hippocampus

AAV5-miHTTAAV5-miScrmiScr miHTT

AAV5-miHTTAAV5-miScrmiScr miHTTAAV5-miHTT induces strong HTT silencing in humanized HD mouse28Target specificity and miHTT efficacyMiniarikova et al, MolTher NA,2016Amber Southwell, UBC75%50%Humanized HD mousemiHTT

128QhHtt - hHtt -

AAV5-miHTT treatment prevents neurodegeneration in HD rat model29Phenotype improvementMiniarikova et al. submitted

AAV5-miHTTAAV5-miSCR

DARPP-32 lesions

AAV5 delivery studies in NHP and HD minipigs

MRI-guided CED delivery to NHP

#

Putamen infusionThalamus infusionSnapshot from the end of the infusion127L207L

MRI-guided CED

13 consecutive acquisitions with 5min delay (total time: min) First cannula placementSecond cannula placementLeftRightThalamus + Putamen infusion

Broad distribution of AAV5-GFP - in NHP

32Transduction efficiency NHP after MRI-CED

8 weeks post bilateral infusion

-GFPAAV5-CAG-GFP127L by CEDAAV5-CAG-GFP207L by CEDValley Biosystems

AAV5-miHTT gene therapy demonstrates efficacy in TgHD minipig study

12 wild-type minipigs12 TgHD minipigs2-3 years of age-202346812-115791110CSFserumCSFserumCSFserumplasmaCSFserumplasmaCSFserumplasmaCSFserumplasmaCSFserumplasmaCSFserumplasmaN=3formulation bufferN=31E+13 GC/pig AAV5-GFPN=31E+13 GC/pig AAV5-miHTTN=33E+13 GC/pig AAV5-miHTTImmunohistochemistry:- GFP- HTT- Iba1- GFAP

DNA isolation: - AAV5 distributionRNA isolation: - miHTT expression- mtHTT reductionProtein isolation:- mtHTT quantitationWeeks:Sampling:Bilateral CED infusionputamen and thalamus

Broad distribution after thalamic injection in pigs34AAV5-GFP transduction efficiency mini pigJan Motlk, Libchov(Evers et al, in preparation)

-GFP

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Broad AAV5-miHTT vector distribution correlates with transgene expression and HTT lowering in HD minipigStrong correlation between vector genome copies and miHTT expression 35

Evers et al, in preparation

AAV5-miHTT treatment results in strong mutant HTT mRNA reduction in TgHD minipig brainEvers et al, in preparation

GLP-TOX studies pathGLP-Tox studies planned in two relevant large brain species

Cynomolgus monkeys - full GLP-TOX study to mimic the clinical trial designTargeting striatum and/or thalamusMRI guided CED infusion filling 80% of structure Vector distributionSafetyHTT lowering and biomarkersMinimum 6 months in-life

HD minipig long term safety, up to 5 years Mimic clinical trial designDemonstrate long term vector persistence Evaluate long-term consequences of HTT loweringGenerate long-term safety data prior product approval

37Gene Therapy is a new technology, so long-term safety is crucial

uniQures HD clinical trial conceptGene transfer will be a therapeutic treatment

Main goal: delay or stop disease progression

Based on the MoA and changes in brain volumes and morphology we propose:

Therapeutic interventions in patients in early HD stages

The concept of early intervention is in discussion with physicians and regulatory agencies. 38Treat patients in early stage of disease progressionJ-P Vonsattel, 1985Atrophy of the striatum (caudate and putamen) Cortical thinningVentricular enlargement

Neuropathology of HD

NormalGrade 2Grade 3Grade 4

caudate and putamen

Acknowledgements and collaboratorsuniQure

Jana MiniarikovaJuliana BronzovaSebastian KuglerMelvin EversJean-Marc BurgunderCynthia BrouwersBernhard Landwermeyer Jolanda SnapperBas BlitsRaygene MartierTom van der ZonSander van DeventerNicole DeglonCharles RichardVirginie ZimmerHarald Petry

Amber SouthwellIlaria Zanella Michael Hayden Angelina Huseinovic Annemart KoornneefPiotr Maczuga Richard van LongesteinHuining LiFlorie BorelEvelyn Hanenmaijer

GHI, MunsterRalf ReilmannIAPG, LibechovJan MotlikStefan JuhasZdenka Eledorova

Taneli HeikkinenOuti KontkanenUCSF/Valley

Ignacio Munoz-SanjuanDouglas MacdonaldDavid Howland

#

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Thank You!

From the uniQure Team

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IONIS-HTTRx: An Antisense Oligonucleotide in Development for the Treatment of Huntingtons Disease03 November 2016Anne Smith, PhDIonis Pharmaceuticals

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Founded: 1989Location: Carlsbad, CA~400 employeesFocus: Drug discovery Early clinical developmentManufacturing

Ionis Pharmaceuticals, Inc.

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The number of new drugs approved by the US FDA per billion dollars (inflation adjusted) spent on research and development from 1950 to 2010.Drug Discovery Productivity is Declining Scannell et al. 2012. Nature Rev Drug Discov.

100101# drugs / billion $ spent0.11950 1960 1970 1980 1990 2000 2010FDA tightens regulation post-thalidomideFirst wave of biotechnology-derived therapiesFDA clears backlog following PDUFA regulations plus small bolus of HIV drugs43

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Drug Discovery Platforms

Small MoleculesProteins

Lipitor

Nucleic Acids

antisense oligonucleotides(ASOs)Gene Therapy

antibodyinsulin44

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DMPKRxRNase HRemoves toxic RNAAntisense Oligonucleotide (ASO) Mechanisms

RNase H1

AntisensemRNA for disease-causing proteinReduces production of a toxic protein

Increases production of a therapeutic protein

Example: IONIS-HTTRxExample: nusinersenExample: IONIS-DMPKRx45

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Broad Clinical ASO Activity in Multiple Tissues46

Ionis Clinical Experience:>6000 subjects dosed>100 clinical studies

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Antisense Technology Uniquely Addresses Challenging Neurological Diseases

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ASOs are Poised to Capitalize on Advances in Biology and Molecular MedicineAdvances in biology dramatic shift in neurologyFrom empiric diagnoses (treat the symptoms)To diagnoses based on understanding of the underlying disease pathophysiology (treat the root cause)Sound translational science to create ASO drugs to genetically-identified targetsBasic science validate target mechanism of the ASOAnimal models test ASO potency, delivery and distribution to the targetdevelop PK/PD models to guide dose selectionClinical studies early assessment of target engagement and effects on disease pathology48

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Ideal target for an ASOHD neuropathology appears to be due to gain-of-toxic function of the mutant huntingtin protein (muHtt)Decreasing muHtt synthesis is expected to target the primary disease mechanismPatients can be identified with certainty via genetic testIONIS-HTTRxAn ASO that targets mRNA transcribed from the human huntingtin geneNot allele-specific; targets both mutant and wild-type huntingtin mRNA

ASO Development for Huntingtons Disease49

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IONIS-HTTRx Activity via RNase H1 Mechanism 50

1

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IONIS-HTTRx: A Generation 2+ ASOA G T C T G A T T CMOEDNAG C A T CG A A C CgapMOE5-wing3-wing

Miller et al. Archives of Neurology, 2008

Gapmer design20 bases DNA in middle (to activate RNase H1)MOE modification at ends51Gen 2+ ASOsDiffusibleStableDose-dependentReversible

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IONIS-HTTRx HistoryYearEvent2003Initiated first neuro program2005Initiated Huntington programScreened for ASOs and tested in mice for tolerability and mRNA knockdownFirst huntingtin-targeting ASOs introduced into HD mouse models2011First medical advisory board meeting to shape IONIS-HTTRx clinical program2013Isis/Roche partnership2015IONIS-HTTRx entered clinical testing in a multi-site Phase 1/2a study

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IONIS-HTTRx: Preclinical Pharmacology and Toxicology SummaryASOs targeting HTT mRNA have pharmacologic activity in mouse models of HDimprove motor function, hypoactivity and stress response in BACHD miceimprove motor function and protect against gene expression changes in YAC128 micepreserve striatal volume and increase survival in R6/2 miceIdentified several ASOs targeting HTT mRNA that are well tolerated in mice (up to 1 year of dosing)ASOs targeting HTT mRNA distribute widely in the non-human primate CNS; huntingtin suppression is well-tolerated53Kordasiewicz et al. 2012, Stanek et al. 2013

Safety/tolerability study in 36 patients Placebo-controlledEach patient receives 4 doses of study drug by IT injection, spaced 28 days apartAfter 4th dose, patients participate in a 4-month post-treatment periodNCT02519036

IONIS-HTTRx First Clinical Study

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IONIS-HTTRx First Clinical Study: Study Progression

Post-Treatment PeriodPost-Treatment PeriodPost-Treatment PeriodPost-Treatment PeriodCohort B(N=8)Cohort C(N=8)Cohort D(N=16)

each represents one dose followed by a 28-day observation period

Cohort A(N=4)

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Primary ObjectiveTo evaluate the safety and tolerability of IONIS-HTTRx in patients with early Huntingtons diseaseSecondary ObjectiveTo characterize the CSF PK of IONIS-HTTRxExploratory ObjectivesTo assess plasma PK properties of IONIS-HTTRxTo explore effects of IONIS-HTTRx on PD markers and on clinical endpoints relevant to HD

IONIS-HTTRx First Clinical Study: Objectives56

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Safety assessments include:Laboratory testsNeurological examsAssessments of cognitive, motor and neuropsychiatric functionVital signsECGPotential markers of target engagement and pharmacodynamic effect include:NeuroimagingClinical, cognitive and functional scalesCSF huntingtin protein and CSF markers of brain health

IONIS-HTTRx First Clinical Study: Assessments57

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First dose in Sept 2015Recently completed enrollment of 3rd dose level and obtained Data Safety Monitoring Board agreement to initiate 4th dose levelStudy completion expected late 2017

IONIS-HTTRx Status of First Clinical Study

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AcknowledgementsThank you to the patients and families who give their time to HD studiesIONIS-HTTRx FIH Clinical Study PIs and KOLsSarah Tabrizi global lead PIRoger Barker, David Craufurd, Bernhard Landwehrmeyer, Blair Leavitt, Carsten Saft, Ed WildRocheChristian Czech, Irene Gerlach, Hansruedi Loetscher, Scott Schobel UCSDDon ClevelandCHDI FoundationRobi Blumenstein, Doug Macdonald, Cristina SampaioIonis PharmaceuticalsFrank BennettHolly KordasiewiczKristin Balogh, Tiffany Baumann, Bethany Fitzsimmons, Sue Freier, Marc Gleichmann, Sarah Greenlee, John Grundy, Scott Henry, Gene Hung, Roger Lane, John Matson, Curt Mazur, Dan Norris, Michael Oestergaard, Erika Paz, Noah Post, Frank Rigo, Punit Seth, Eric Swayze, Ed Wanciewicz, Andy Watt, Tom Zanardi

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