®

Supported by a grant from Endo Pharmaceuticals, Inc., USA

Editorial Board

Editor-in-Chief

Jane C. Ballantyne, MD, FRCAAnesthesiology, Pain MedicineUSA

Advisory Board

Michael J. Cousins, MD, DSCPain Medicine, Palliative MedicineAustralia

Maria Adele Giamberardino, MD Internal Medicine, Physiology Italy

Robert N. Jamison, PhD Psychology, Pain Assessment USA

Patricia A. McGrath, PhD Psychology, Pediatric Pain Canada

M.R. Rajagopal, MDPain Medicine, Palliative MedicineIndia

Maree T. Smith, PhD Pharmacology Australia

Claudia Sommer, MDNeurologyGermany

Harriët M. Wittink, PhD, PT Physical Therapy The Netherlands

Production

Elizabeth Endres, Associate Editor

Kathleen E. Havers, Programs Coordinator

Karen Smaalders, Marketing and Communications Manager

Upcoming Issues

Pharmacogenetics

Vol. XVIII, Issue 8 September 2010

Opioid SensitivityNeuropathic Cancer PainDealing with Suff ering

Analgesic drug dosing requirements to produce satisfactory pain relief with tolerable side-effects are subject to considerable interindividual variability—even in patients with pain of an apparently similar type and intensity. Contributing factors include those of genetic and environmental origin as well as their interaction (Fig. 1). Envi-ronmental factors include patient age, sex, status of liver and kidney function, lifestyle variables such as smoking and alcohol consumption, disease comorbidities, and con-current medications.1,2 Genetic factors include those related to the regulation of anal-gesic drug pharmacodynamics and pharmacokinetics.2-6

Genotype and Phenotype: Defi nitionsAn individual’s genotype is the inheritable information encoded in a particular set of genes on 23 pairs of chromosomes particular to the individual. Each person has a unique genomic fi ngerprint comprising two copies of each gene, except for the sex-linked genes. Each gene has a specifi c locus on a given chromosome, and each gene can have multiple alleles whose relative frequencies may vary markedly among ethnic groups in the general population.5 By contrast, an individual’s phenotype constitutes the observable characteristics or physical manifestations of his or her genotype.

Single-Nucleotide PolymorphismsA single-nucleotide polymorphism (SNP) is a DNA sequence variation at a single location in the genome resulting in two allelic variants (Fig. 2), with the least com-mon allele occurring at a frequency of at least 1% in the general population.5 The contribution of individual SNPs to observations of drug ineffi cacy or excessive tox-icity in population subgroups (i.e., different patient phenotypes) constitutes the fi eld of pharmacogenetics.5,6

SNPs in genes encoding drug-metabolizing enzymes, efflux transporters in the blood-brain barrier, analgesic drug

targets, and neurotransmitter pathways all may contribute to interindividual variability in analgesic drug dosing

requirements and adverse event profiles

Since sequencing of the human genome almost a decade ago,7,8 there have been signifi cant advances in genotyping technologies, which led to predictions that point-of-care devices would become available for genotyping patients to enable

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clinicians to individually tailor drug therapy. However, this goal has yet to be achieved in the analgesics fi eld due to the complexity produced by the multiplicity of SNPs in genes encoding drug metabolism enzymes, transporters, receptors, ion channels, and neurotransmitter systems, all of which have the potential to concurrently affect pain relief outcomes in in-dividuals. Hence, it is diffi cult to predict, a priori, the impact of concurrently occurring SNPs in multiple genes of interest on the pharmacokinetics and pharmacodynamics of analgesic agents in individuals.

Pharmacogenetics Research in HumansInsight from human pharmacogenetics research in the analge-sics fi eld comes from studies designed to examine the possible infl uence of SNPs in genes of interest on (i) interindividual dif-ferences in analgesic drug pharmacokinetics and experimental pain thresholds in healthy subjects and (ii) pharmacodynamic outcomes in patients with clinical pain.

In healthy human volunteers, quantitative sensory testing (QST) is used to determine experimental pain thresholds or stimulus-response curves for sensory processing across a range of pain modalities including thermal, mechanical, electrical, and chemi-cal stimuli.9 More sophisticated designs employing QST involve

application of these stimuli to a range of tissue types including skin, muscles, and viscera to produce a mosaic of responses.9 QST has been used in volunteer studies not only to assess the infl uence of genetic factors on interindividual variability in pain thresholds but also to defi ne pharmacokinetic-pharmacodynamic relationships for analgesic agents of interest.

The following sections present an overview of fi ndings to date on major research themes in the pharmacogenetics fi eld relevant to interindividual variability in analgesic drug dosing requirements.

Genetic Factors and PharmacokineticsAfter oral dosing, analgesic drugs are absorbed across the gas-trointestinal mucosa into the portal circulation and delivered directly to the liver (Fig. 3). In the process, absorbed drugs are exposed to an array of metabolic enzymes found in the gastro-intestinal mucosa and the liver. The fraction of the dose that es-capes fi rst-pass metabolism enters the systemic circulation (Fig. 3). From there, an absorbed analgesic agent may diffuse across the tight junctions of the blood-brain barrier (BBB) to interact with central nervous system (CNS) receptors to produce both analgesia and adverse effects. For centrally acting analgesics that are substrates for drug transporters residing in the BBB, the amount of drug entering the brain is reduced by opposing effl ux mechanisms mediated by transporters such as P-glycoprotein that are located in the BBB. Pharmacogenetics research has shown that SNPs in genes encoding drug-metabolizing enzymes, effl ux transporters in the BBB, analgesic drug targets, and neu-rotransmitter pathways all have the potential to contribute con-currently to interindividual variability in analgesic drug dosing requirements and adverse-event profi les.

Analgesic Drugs and MetabolismThe metabolism of analgesic agents involves enzyme-catalyzed changes in their chemical structure to increase water solubility and facilitate excretion from the body as a key step in terminating drug action. Drug metabolism reactions are subdivided into Phase 1 “functionalization” reactions (e.g. oxidation, reduction, and hydrolysis) and Phase 2 metabolism to form water-soluble gluc-uronic acid, sulfate, and/or glutathione conjugates that are read-ily excreted via the kidney.4 In some instances, metabolism may result in bioactivation to form analgesically active metabolites, such as the metabolism of morphine to morphine-6-glucuronide, the metabolism of codeine to morphine, or the metabolism of tramadol to its M1 metabolite.10 Active metabolites may also con-tribute to adverse-event profi les such as the metabolism of pethi-dine (meperidine), morphine, and hydromorphone to their neu-roexcitatory metabolites, norpethidine, morphine-3-glucuronide, and hydromorphone-3-glucuronide, respectively.11

The Cytochrome P450 Superfamily of Phase 1 Drug-Metabolizing EnzymesThe cytochrome P450 (CYP) superfamily of enzymes catalyzes Phase 1 metabolism of a wide range of endogenous and exogenous

Fig. 1. Schematic diagram illustrating that gene-environment interactions have the potential to infl uence the observed phenotype.

genetics

phenotype

environment

C T G

A C

AA

TT G T T

A A

G G

C C

C G

C

AA

TT G T T

A A

G

CTT

AA

SNP

Fig. 2. Schematic diagram illustrating a C to T single nucleotide polymorphism (SNP) in DNA.

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molecules.12 In the human genome, there are 57 functional CYP genes and 58 CYP pseudogenes within 18 families (i.e., CYP families 1–5, 7, 8, 11, 17, 19–21, 24, 26, 27, 39, 46, and 51),6 with six CYP isoforms known to have signifi cant roles in the metabolism of clinically used medications, viz CYP1A2, CYP2D6, CYP2C9, CYP3A4, CYP2E1, and CYP2A6.13 SNPs have been identifi ed in most CYP isoforms, with their allelic variants resulting in altered protein expression and/or enzy-matic activity (see www.cypalleles.ki.se). Although CYP2D6 is a minor constituent (2–4%) of hepatic CYP proteins in humans,14 it has an important role in the metabolism of ~25% of currently used medications, including many agents used to treat pain. Genetic variability in the CYP2D6 gene has been intensively studied in humans.3,15

Functionally, the presence of an allelic variant in a particular CYP isoform will result in one of four drug-metabolizing phenotypes: poor metabolizer (PM), intermediate metabolizer

(IM), extensive metabolizer (EM), or ultrarapid metabolizer (UM)

Human Drug Metabolizer PhenotypesFunctionally, the presence of an allelic variant in a particular CYP isoform will result in one of four drug-metabolizing phe-notypes: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), or ultrarapid metabolizer (UM). The

corresponding genotypes are: PMs have two nonfunctional (null) alleles, IMs have at least one reduced-functional allele, EMs (normal individuals) have at least one functional allele, and UMs have multiple copies of a functional allele and/or an allele where the mutation confers increased gene transcription.15,16 For drugs where CYP2D6-catalyzed metabolism is a major clearance mech-anism, individuals with a PM phenotype are at risk of adverse drug reactions or toxicity at regular doses, whereas those with the UM phenotype will require higher doses to achieve therapeutic plasma drug concentrations.6

CYP2D6 SNPsTo date, more than 80 distinct allelic variants of the CYP2D6 gene have been identifi ed, resulting in a broad range of pheno-typic diversity within populations characterized by marked dif-ferences between ethnic groups.17,18 In brief, the frequency of the PM phenotype is in the order of Caucasian (7–11%) > African American and Hispanic > Indian > South-Eastern and Eastern Asia > Chinese, Korean, and Japanese (0–1.2%) populations.6,18-25 The frequency of the UM phenotype is in the order of Black Ethi-opian and Saudi Arabian (16–20%) > Sicilian, Italian, Spanish, Mediterranean, and Turkish > Caucasian and African American > European Caucasian (1–2%) populations.6,18,23,26–31 However, the genotype-phenotype relationship of most CYP2D6 alleles is not yet well established.

Analgesic agents where SNPs in the CYP2D6 gene may infl u-ence patient outcomes include tramadol, codeine, tricyclic an-tidpressants, venlafaxine, and antiarrythymics, as well as other

Fig. 3. Schematic diagram summarizing how polymorphisms in genes encoding drug metabolism enzymes, transporters in the blood-brain barrier, as well as target receptors and neurotransmitter systems have the po-tential to concurrently alter desired and undesired effects produced by analgesic agents in a complex manner in individual patients.

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agents such as antiemetics (e.g., ondansetron), tamoxifen, and antipsychotics (e.g., risperidone).6 Several examples are out-lined below.

TramadolAfter systemic administration, tramadol is metabolized by CY-P2D6 to its O-demethylated metabolite, O-desmethyltramadol (M1, Fig. 4A), which is a potent μ-opioid receptor agonist.10 CYP2D6 PMs are expected to experience less analgesia after standard doses and to have higher tramadol dosing requirements to achieve satisfactory pain relief relative to EM individuals.32,33 After oral tramadol dosing in humans, plasma concentrations of M1 are higher in EMs compared with PMs, whereas M1 forma-tion is increased in UMs, who are at higher risk for developing opioid-related side effects.34,35

CodeineCodeine is generally thought to be a prodrug for its O-demeth-ylated metabolite, morphine, with up to 10% of a dose being metabolized to morphine (Fig. 4B) by CYP2D6.36–38 In CYP2D6 PMs, morphine levels are virtually undetectable, and codeine reportedly lacks effi cacy.39-42 By contrast, codeine is extensively metabolized to morphine in UM individuals, raising the risk of respiratory depression after regular doses of codeine.43 In an extreme case involving a breastfed neonate of a UM mother ad-ministered codeine, high levels of morphine were produced in the neonate, resulting in mortality.44 Subsequently, the authors of a case-controlled study recommended that codeine should not be prescribed to breast-feeding mothers.45

OxycodoneOxycodone is a strong opioid analgesic that is widely used to treat moderate to severe pain. Although ∼10% of an oxyco-done dose undergoes CYP2D6-catalyzed O-demethylation to oxymorphone (Fig. 4C), a potent μ-opioid receptor agonist, the circulating plasma concentrations of metabolically derived oxymorphone are very low (∼1 ng/mL) in EMs and threefold lower (0.3 ng/mL) in PMs.46 Although animal studies show that oxycodone administered directly into the cerebrospinal fl uid of the rat brain produces dose-dependent naloxone-sensitive antinociception,47 the notion that oxycodone, rather than meta-bolically derived oxymorphone, is responsible for the analgesic effects of oxycodone in humans has been discounted by some authors. Recent pharmacogenetics research in healthy human subjects as well as in patients with postoperative pain has pro-vided useful insight into this issue. In a study conducted in a group of 10 healthy volunteers comprising six EMs, one IM, one PM, and two UMs, antinociceptive responses to electrical stimulation and tolerance to the cold pressor test appeared to be signifi cantly correlated with CYP2D6 phenotype such that the two UMs experienced superior analgesia relative to EMs and the single PM had lower antinociceptive responses relative to the EMs.48 However, the relevance of these fi ndings to relief of postoperative pain appears limited, because a recent much larger clinical study involving administration of oxycodone to 270 patients (24 PMs and 246 EMs) for postoperative pain re-lief showed that analgesic outcomes did not differ signifi cantly between CYP2D6 PM and EM individuals.49 These fi ndings show unequivocally that oxycodone itself, rather than metaboli-cally derived oxymorphone, underpins oxycodone’s ability to alleviate clinical pain.

MexiletineMexiletine undergoes extensive metabolism to largely inactive metabolites, with formation of hydroxymethylmexiletine and parahydroxymexiletine catalyzed predominantly via CYP2D6 (Fig. 4D).6 Mexiletine has a very narrow therapeutic plasma concentration range (0.5–2 μg/mL), and so downward adjust-ment of standard doses is required in PMs relative to EMs to avoid toxicity.6

OCH3

OH

CH3

CH3

OH

OH

CH3

CH3

N N

CH3O

CH3

O

C H 3N

OH O H

N

O H

CH 3

OHOH

OH O

C H3

CH3

NN

OO

O

CH3

NH2

CH3 CH3

OH

CH2OH

CH3

NH2

NH2

CH3

CH3

CH3

CH3

O

O

O

Tramadol M1

Codeine Morphine

Oxycodone Oxymorphone

Mexiletine

p-Hydroxymexiletine

Hydroxymethylmexiletine

A

B

C

D

Fig. 4. CYP2D6-catalyzed metabolism of (A) tramadol to its M1 metabolite, (B) co-deine to its active metabolite morphine, (C) oxycodone to its minor metabolite oxy-morphone, and (D) mexiletine to its inactive hydroxylated metabolites.

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Phase 2 Drug-Metabolizing Enzymes: The UGT SuperfamilyIn humans, Phase 2 metabolism of endogenous molecules such as bilirubin, bile acids, fatty acids, and steroid hormones, as well as that of many commonly prescribed medications, is characterized by considerable interindividual variability. Phase 2 metabolism is catalyzed by members of the uridinediphosphoglucuronosyltrans-ferase (UGT) superfamily of enzymes to form water-soluble gluc-uronide conjugates.50,51 There are two major UGT enzyme classes in humans—UGT1A and UGT2—with at least eight isoforms of UGT1A (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, and 1A10) and seven isoforms of UGT2 (UGT2A1, 2B4, 2B7, 2B10, 2B11, 2B15, and 2B17) having been identifi ed.52 Of these, UGT2B7 has a key role in the metabolism of opioid analgesics such as morphine and hydromorphone, nonsteroidal anti-infl ammatory drugs, and anticonvulsants with this isoform being abundantly ex-pressed in the gastrointestinal mucosa and the liver.53,54 Although pharmacogenetics research on variants in UGT genes to date has revealed considerable complexity, interpretation is diffi cult and ongoing research is required.51

Drug Transporters in the Blood-Brain BarrierEffl ux drug transporters such as P-glycoprotein that are located in the BBB have evolved to protect the brain from toxins of envi-ronmental and dietary origin. Most effl ux transporters belong to the adenosine triphosphate (ATP)-binding cassette (ABC) super-family of membrane proteins that infl uence the intracellular con-centration of a broad array of compounds in cells and tissues.55 To date, 49 members of the ABC-transporter family, subdivided into seven subfamilies, A–G, have been identifi ed (http://nutrigene.4t.com/humanabc.htm).55,56 The ABC transporter P-glycoprotein (ABCB1) is the best-characterized human drug transporter, with reports of more than 50 SNPs and several insertion/deletion polymorphisms in the ABCB1 gene.55 P-glycoprotein plays an important role in the BBB effl ux transport of a range of clinically used drugs, including antidepressants, steroids, digoxin, and cyto-statics.55,57 Pharmacogenetic studies show considerable between-study variability with regard to the infl uence of a particular SNP in the ABCB1 gene on pharmacokinetic and pharmacodynamic outcomes, making it diffi cult to draw conclusions.55,57

The mechanism through which lower COMT activity appears to reduce opioid analgesic dosing requirements is multifactorial, with

potential effects at multiple levels of the neuraxis

SNPs and Analgesic Drug Pharmacodynamic OutcomesIn the pharmacogenetics fi eld, considerable research efforts in the last decade have focused on assessing the infl uence of SNPs in the genes encoding the μ-opioid receptor and to a lesser extent,

the enzyme catechol-O-methyl-transferase (COMT), on inter-individual differences in opioid dosing requirements as well as reported levels of pain.

Receptor/Ion Channel Polymorphisms: OPRM1 (Mu-Opioid Receptor)Many strong opioid analgesics produce analgesia by activating the μ-opioid receptor in a manner similar to morphine.58 To date, ∼1800 variants in OPRM1, the gene encoding the μ-opioid re-ceptor, have been identifi ed, with more than 20 of these variants being SNPs producing amino-acid changes.2,59 One OPRM1 SNP that occurs at the A118G position (N40D variant) is relatively common, with the rare allele occurring in approximately 20–30% of the population.60 Although initial genetic association studies suggested its functional importance,61 subsequent studies either did not replicate or only partially replicated the earlier fi ndings. Recently, the relevance of the OPRM1 A118G genetic variant for the management of clinical pain has been seriously questioned because a meta-analysis found no consistent association between OPRM1 A118G genotypes and most of the phenotypes (opioid dosing, pain, and side effects) across the studies reviewed.62 Al-though there appeared to be an association between less nausea and increased opioid dosing requirements for homozygous car-riers of the N40D variant, the correlation was weak.62 Hence, OPRM1 genotyping of patients to facilitate individual tailoring of opioid analgesic dosing requirements is not supported by research fi ndings to date.63

SNPs and Neurotransmitter Pathways: COMTCatechol-O-methyl transferase (COMT) is an enzyme that cata-lyzes the metabolism of endogenous catecholamine neurotrans-mitters such as epinephrine, norepinephrine, and dopamine that have important roles in nociceptive signal transduction and an-algesia.64 A functional valine-to-methionine SNP at position 158 (V158M) in COMT (called rs4680) is associated with a three- to fourfold reduction in COMT activity and appears to be linked to a requirement for lower doses of morphine to attain satisfac-tory relief of cancer pain.65,66 In one study, this SNP appeared to be associated with an increased sensitivity to painful stimuli, but subsequent studies failed to show a genetic association with post-surgical pain, chronic widespread pain, or experimental pain.67–69 The mechanism through which lower COMT activity appears to reduce opioid analgesic dosing requirements is multifactorial, with potential effects at multiple levels of the neuraxis.66,70 These effects include enhanced descending noradrenergic inhibition, as well as enhanced dopaminergic signaling, resulting in reduced neuronal enkephalin concentrations, followed by an upregulation of opioid receptors.66,70

Sodium Channel Mutations and Pain SensitivityLocal anesthetics such as lidocaine and antiarrhythmics such as mexiletine produce their pain-relieving effects via blockade of voltage-gated sodium channels in sensory nerves. However,

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they may also produce a range of unwanted effects, includ-ing motor block, cardiac conduction block, and neurotoxicity, through inhibition of sodium channels in motor nerves, cardiac tissue, and the brain. Of the nine sodium channel subtypes iden-tifi ed to date, NaV1.3, NaV1.7, NaV1.8, and NaV1.9 appear to be mainly expressed in sensory nerves, and so novel analgesics targeted to these sodium channel subtypes have the potential to have more favorable adverse-event profi les while retaining analgesic effi cacy.71-73 Support for this approach comes from hu-man pharmacogenetics research, whereby individuals with rare loss-of-function or gain-of-function mutations in the SCN9A gene that encodes the NaV1.7 sodium channel subtype,74 present with one of two extreme pain phenotypes—an inability to sense pain or a familial chronic pain syndrome, respectively.75 These observations raised the possibility that SNPs in the SCN9A gene may correlate with levels of clinical pain reported by patients. In support of this notion, a recent genetic study involving 1,277 individuals across fi ve different patient cohorts with a variety of pain conditions (osteoarthritis, sciatica, pancreatitis, post-diskectomy pain, and phantom limb pain) found a signifi cant association between the SCN9A SNP, rs6746030 (G/A substitu-tion), and pain perception.74 Individuals with the rarer A allele reported higher pain scores compared with individuals with the more common G allele.74 Collectively, human pharmacogenet-ics research points to an important role for the NaV1.7 sodium channel subtype in the modulation of clinical pain, which vali-dates drug discovery programs targeted to the development of NaV1.7 blockers as future analgesic agents.

Collectively, human pharmacogenetics research points to an important role for the NaV1.7

sodium channel subtype in the modulation of clinical pain, which validates drug discovery

programs targeted to the development of NaV1.7 blockers as future analgesic agents

ConclusionsPharmacogenetics research conducted in humans over the past decade has provided important insight into the multiplicity of genetic factors that contribute to the often marked interindividual differences in analgesic dosing requirements for patients with clinical pain of apparently similar type and intensity. These ge-netic factors include those affecting analgesic drug metabolism, transport of analgesic agents across the BBB, and their activity at target receptors and ion channels and in the modulation of neu-rotransmitter pathways.

Extrapolation from the fi ndings of genetics research conducted in very large numbers of subjects for other complex disorders, such as diabetes,76 suggests that the genetic component to interindi-vidual variability in analgesic dosing requirements and reported levels of clinical pain is probably underpinned by concurrent small differences in a very large number of genes. Although the

technology to routinely genotype patients and identify a large number of genetic variants is within reach, clinical application of the data so generated to enable tailoring of analgesic dosing regimens in individual patients is still some way off. Progress in this area will require cost reduction as well as development and validation of robust methods not only for producing an inte-grated interpretation of an individual’s pharmacogenetic profi le but also for determining its susceptibility to modulation by en-vironmental factors.

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Timely topics in pain research and treatment have been selected for publication, but the information provided and opinions expressed have not involved any verifi cation of the fi ndings, conclusions, and opinions by IASP. Thus, opinions expressed in Pain: Clinical Updates do not necessarily refl ect those of IASP or of the Offi cers or Councilors. No responsibility is assumed by IASP for any injury and/or damage to persons or property as a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of the rapid advances in the medical sciences, the publisher recommends independent verifi cation of diagnoses and drug dosages.

For permission to reprint or translate this article, contact:International Association for the Study of Pain • 111 Queen Anne Avenue North, Suite 501, Seattle, WA 98109-4955 USA

Tel: +1-206-283-0311 • Fax: +1-206-283-9403 • Email: iaspdesk@iasp-pain.org • www.iasp-pain.org

Copyright © 2010. All rights reserved. ISSN 1083-0707.

Printed in the U.S.A.

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75. Cheng X, Dib-Hajj SD, Tyrrell L, Wright DA, Fischer TZ, Waxman SG. Mutations at opposite ends of the DIII/S4-S5 linker of sodium channel NaV1.7 produce distinct pain disorders. Mol Pain 2010;6:24.

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Maree T. Smith, PhD, and Arjun Muralidharan, B Pharm (Hons)The University of Queensland Centre for Integrated Preclinical Drug Development and School of Pharmacy Brisbane, Queensland, AustraliaEmail: maree.smith@uq.edu.au

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