List of benzimidazole opioids

Last updated

Benzimidazole opioids, also known as nitazenes, are a class of synthetic opioids with an unusual benzimidazole structure often referred to as "opioid New Psychoactive Substances", or "opioid NPS". [1] [2]

Contents

First synthesized in the 1950s by CIBA Pharmaceuticals as potential analgesic medications, several substances in the class have been identified, the best known being etonitazene. [3] [1] Like other synthetic opioids, benzimidazole opioids bind the mu-opioid receptor and may exhibit potency up to several hundred times that of morphine. [4] [5] [6] [7] [8] While several substances in this class have found applications in research, they have never been used in clinical medicine due to their profound risk of respiratory depression and death. [9]

In the early 2020s, the substance has been recognized as emerging drugs of abuse. [10] [11] [12] Isotonitazene was first identified in samples of illicit drugs, and implicated in opioid overdose deaths in Europe, Canada, and the United States beginning in 2019. [13] Previously known nitazene analogs such as metonitazene and butonitazene, as well as novel nitazenes not previously described in the scientific or patent literature, have since been discovered in toxicologic samples during forensic investigations. [12] Nitazene analogs have been found in pills missold as other drugs, such as benzodiazepines, in the United Kingdom [14] and New Zealand. [15]

Structure-activity relationship

The structure-activity relationship of the drug class has been explored to a reasonable extent. The optimal substitution pattern is fairly tightly defined (i.e. N,N-diethyl on the amine nitrogen, 4-ethoxy on the benzyl ring and 5-nitro on the benzimidazole ring), but even derivatives incorporating only some of these features are still potent opioids. If a methyl or carboxamide group is added on the alpha carbon of the benzyl group, or the benzyl is replaced by 2-phenylethyl, compounds of similar activity are obtained. Relative analgesic activity values are derived from tests on mice and cannot be extrapolated directly to humans, though the same general activity trends apply. [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [ excessive citations ]

A 2019 publication [27] has shown the possibility the previously assumed binding position of the benzimidazole class, [28] acting as a semi-rigid fentanyl analogue may be incorrect. Based on a large scale analysis of known opioid receptor ligands a template was created through manual overlaying and alignment which has identified several mu-specific areas within the receptor. In this analysis, it is noted, etonitazene now more closely matches another, separate mu-specific region, sharing only a small area in common with the fentanyl class.

Abuse

In the UK, abuse of nitazene analogues emerged in 2023 as an important cause of drug-overdose death, with it being linked to 54 deaths over a 6-month period. [29] Most of the deaths have occurred outside London, the source of supply is thought to be by post from laboratories in China and some of the deaths have been associated by the mislabelling of nitazenes as fentanyl. While compounds from this class are sometimes incorrectly referred to as "nitazene", [30] the 4 unsubstituted compound nitazene itself is of relatively low potency and has not been reported as a designer drug, with most cases of abuse and overdose linked to more potent derivatives such as metonitazene, protonitazene, isotonitazene, etonitazepyne and etodesnitazene.

Table of benzimidazole opioids

Nitazene general.png

Chemical structureDrug nameRing substitutionAnalgesic potency (morphine = 1)PubChemCAS number
DEAE-BN-BI structure.png Desnitazene (1-diethylaminoethyl-2-benzyl-benzimidazole)hydrogen0.1 28787 17817-67-3
Metodesnitazene structure.png Metodesnitazene (Metazene)4-methoxy1 26412 14030-77-4
1071546-40-1 (HCl)
Metodesnitazepyne structure.png Metodesnitazepyne 4-methoxy
Etazene.svg Etodesnitazene (Etazene)4-ethoxy70 149797386 14030-76-3
Pyrrolidine-etodesnitazene structure.png Etodesnitazepyne 4-ethoxy20 162623599
Piperidine-etodesnitazene structure.png Etodesnitazepipne 4-ethoxy10 162623611 102762-98-1
Protodesnitazene structure.png Protodesnitazene 4-(n-propoxy)10 157010653 805212-21-9
Isotodesnitazene structure.png Isotodesnitazene 4-isopropoxy~75 162623708 2732926-27-9
Nitazene structure.png Nitazene hydrogen 2 15327524 14030-71-8
Ethylene-nitazene structure.png Ethylene nitazenehydrogen 15327525
Meta-metonitazene structure.png meta-Metonitazene 3-methoxy2
Metonitazene.svg Metonitazene 4-methoxy 100 53316366 14680-51-4
Metonitazepyne structure.png Metonitazepyne 4-methoxy
Metonitazepipne structure.png Metonitazepipne 4-methoxy
N-Desethylmetonitazene structure.png N-Desethylmetonitazene 4-methoxy
Metomethazene structure.png Metomethazene 4-methoxy
Dimetonitazene structure.png Dimetonitazene 3,4-dimethoxy10 162623836 95809-33-9
Alpha-methyl-metonitazene structure.png α-methyl-metonitazene 4-methoxy50 162625089 806634-80-0
Alpha-methyl-etonitazene structure.png α-methyl-etonitazene4-ethoxy
Alpha-hydroxy-etonitazene structure.png α-hydroxy-etonitazene4-ethoxy 21815907
Phenethyl-metonitazene structure.png Metonitazene phenethyl homologue (Ethylene metonitazene)4-methoxy50
Ethylene-etonitazene structure.png Ethylene etonitazene4-ethoxy
Etonitazene.svg Etonitazene 4-ethoxy 1000-1500 13493 911-65-9
O-desmethyl-etonitazene structure.png O-Desethyl-etonitazene 4-hydroxy 1 156588969 94758-81-3
N-desethyletonitazene structure.png N-Desethyletonitazene (NDE)4-ethoxy1000/1500-2000 162623580 2732926-26-8
5-Amino-etonitazene structure.png Etonitazene 5-amino metabolite 4-ethoxy2 13408927
Etomethazene structure.png Etomethazene 4-ethoxy20 168310446 95293-25-7
Etotriflazene structure.png Etonitazene 5-trifluoromethyl analogue (Etotriflazene) [31] 4-ethoxy 21815908
Isototriflazene structure.png 5-Trifluoromethyl isotodesnitazene4-isopropoxy
Etocyanazene structure.png Etonitazene 5-cyano analogue (Etocyanazene) [32] 4-ethoxy 27268 15419-87-1
Etoacetazene structure.png Etonitazene 5-acetyl analogue (Etoacetazene) [33] 4-ethoxy 25957 13406-60-5
Etodicloazene structure.png Etonitazene 5,6-dichloro analogue (Etodicloazene)4-ethoxy
Dimethyl-etonitazene structure.png Etonitazene N,N-dimethyl analogue 4-ethoxy20 67089584 714190-52-0
Etonitazepyne structure.png Etonitazepyne 4-ethoxy180-190 155804760 2785346-75-8
Piperidine-etonitazene structure.png Etonitazepipne 4-ethoxy190 [34] 162623834 734496-28-7
Morpholine-etonitazene structure.png Etonitazene morpholine analogue4-ethoxy2 162623685 805958-08-1
Ethylpyrrolidinylmethyl-etonitazene structure.png 1-Ethyl pyrrolidinylmethyl N-desalkyl etonitazene4-ethoxy
6-Nitro-etonitazene structure.png Etonitazene 6-nitro isomer (iso-etonitazene) [35] 4-ethoxy20 59799752 114160-61-1
Protonitazene structure.png Protonitazene 4-(n-propoxy)200 156589001 119276-01-6
95958-84-2
Protonitazepyne structure.png Protonitazepyne 4-(n-propoxy)180-190 168322728
Protonitazepipne structure.png Protonitazepipne 4-(n-propoxy)
N-Desethylprotonitazene structure.png N-Desethylprotonitazene 4-(n-propoxy)
Isotonitazene.svg Isotonitazene 4-isopropoxy500 145721979 14188-81-9
Isotonitazepyne structure.png Isotonitazepyne 4-isopropoxy 168322631
Isotonitazepipne structure.png Isotonitazepipne 4-isopropoxy
N-desethyl-isotonitazene structure.png N-Desethylisotonitazene 4-isopropoxy1000-2000 162623899 2732926-24-6
Isoisotonitazene structure.png iso-isotonitazene4-isopropoxy
Butonitazene structure.png Butonitazene 4-butoxy5 156588955 95810-54-1
Isobutylnitazene structure.png Isobutonitazene 4-isobutoxy 168322282
Secbutylnitazene structure.png Secbutonitazene 4-secbutoxy 168322285
Etoetonitazene structure.png Etoetonitazene 4-ethoxyethoxy50 162623504 806642-21-7
Fluornitrazene structure.png Fluornitrazene [36] 4-(2-fluoroethoxy) 172332078
Trifluorometonitazene structure.png Trifluorometonitazene4-trifluoromethoxy
Fluonitazene structure.png Flunitazene 4-fluoro1 156588967 2728-91-8
Clonitazene Structural Formula V1.svg Clonitazene 4-chloro 3 62528 3861-76-5
Diclonitazene structure.png Diclonitazene 2,4-dichloro
Alpha-CONH2-clonitazene structure.png α-carboxamido-clonitazene 4-chloro3
Bronitazene structure.png Bronitazene 4-bromo5 162623726
Nitronitazene structure.png Nitronitazene 4-nitro
Methylnitazene structure.png Methylnitazene (Menitazene)4-methyl 10 162623683 95282-00-1
Ethylnitazene structure.png Ethylnitazene (Enitazene)4-ethyl 20 162623845 114160-82-6
Propylnitazene structure.png Propylnitazene (Pronitazene)4-propyl50 162623877 700342-00-3
Tbutylnitazene structure.png t-Butylnitazene 4-(tert-butyl)2 162623621 805215-64-9
Acetoxynitazene structure.png Acetoxynitazene 4-acetoxy 5 162623779 102760-24-7
Methylthionitazene structure.png Methionitazene 4-methylthio50 162623790 102471-37-4
Ethylthionitazene structure.png Ethylthionitazene 4-ethylthio30 162623931 102758-70-3
Phenylthio-etazene structure.png Etodesnitazene phenylthio analogue 4-ethoxy1 21045 3275-92-1
Phenylthio-etazene-pyrrolidine structure.png Etodesnitazene phenylthio / pyrrolidine analogue 4-ethoxy2 19846499 13451-68-8
Methylenedioxynitazene structure.png Methylenedioxynitazene [37] 3,4-methylenedioxy
Tetrahydrofuranitazene structure.png Ethyleneoxynitazene [38] fused tetrahydrofuran

See also

Related Research Articles

<span class="mw-page-title-main">Etonitazene</span> Chemical compound

Etonitazene, also known as EA-4941 or CS-4640, is a benzimidazole opioid, first reported in 1957, that has been shown to have approximately 1,000 to 1,500 times the potency of morphine in animals.

<span class="mw-page-title-main">Lofentanil</span> Opioid analgesic

Lofentanil or lofentanyl is one of the most potent opioid analgesics known and is an analogue of fentanyl, which was developed in 1960. It is most similar to the highly potent opioid carfentanil (4-carbomethoxyfentanyl), only slightly more potent. Lofentanil can be described as 3-methylcarfentanil, or 3-methyl-4-carbomethoxyfentanyl. While 3-methylfentanyl is considerably more potent than fentanyl itself, lofentanil is only slightly stronger than carfentanil. This suggests that substitution at both the 3 and 4 positions of the piperidine ring introduces steric hindrance which prevents μ-opioid affinity from increasing much further. As with other 3-substituted fentanyl derivatives such as ohmefentanyl, the stereoisomerism of lofentanil is very important, with some stereoisomers being much more potent than others.

<span class="mw-page-title-main">Clonitazene</span> Opioid analgesic

Clonitazene is an opioid analgesic of approximately three times the potency of morphine. It is related to etonitazene, an opioid of significantly higher potency. Clonitazene is not currently marketed. It is a controlled substance; in the United States it is a Schedule I Narcotic controlled substance with a DEA ACSCN of 9612 and an established manufacturing quota of 25 grams for 2022.

<span class="mw-page-title-main">Mirfentanil</span> Chemical compound

Mirfentanil is a fentanyl derivative with strong selectivity for the μ opioid receptor. At lower doses, it antagonizes the analgesic effects of alfentanil and substitutes for naloxone in morphine-treated monkeys; however, it also reverses naloxone-precipitated withdrawal in pigeons trained to discriminate morphine from naloxone.

<span class="mw-page-title-main">IBNtxA</span> Chemical compound

IBNtxA, or 3-iodobenzoyl naltrexamine, is an atypical opioid analgesic drug derived from naltrexone. In animal studies it produces potent analgesic effects that are blocked by levallorphan and so appear to be μ-opioid mediated, but it fails to produce constipation or respiratory depression, and is neither rewarding or aversive in conditioned place preference protocols. These unusual properties are thought to result from agonist action at a splice variant or heterodimer of the μ-opioid receptor, rather than at the classical full length form targeted by conventional opioid drugs.

<span class="mw-page-title-main">Metonitazene</span> Chemical compound (analgesic drug)

Metonitazene is an analgesic compound related to etonitazene, which was first reported in 1957, and has been shown to have approximately 1000 times the potency of morphine by central routes of administration, but if used orally it has been shown to have approximately 10 times the potency of morphine.

<span class="mw-page-title-main">Isotonitazene</span> Chemical compound

Isotonitazene is a benzimidazole-derived opioid analgesic drug related to etonitazene, which has been sold as a designer drug. It has only around half the potency of etonitazene in animal studies, but it is likely even less potent in humans as was seen with etonitazene. Isotonitazene was fully characterized in November 2019 in a paper where the authors performed a full analytical structure elucidation in addition to determination of the potency at the μ-opioid receptor using a biological functional assay in vitro. While isotonitazene was not compared directly to morphine in this assay, it was found to be around 2.5 times more potent than hydromorphone and slightly more potent than fentanyl.

<span class="mw-page-title-main">Brorphine</span> Chemical compound

Brorphine is a piperidine-based opioid analgesic compound. Brorphine was originally discovered in a 2018 paper investigating functionally biased opioid compounds, with the intention of finding safer analgesics that produce less respiratory depression than typical opioids. Brorphine was originally reported to be highly biased, with an EC50 of 4.8nM for GTPγS binding and 182nM for β-arrestin recruitment, however a more recent study found no significant bias for any of the compounds tested, including brorphine. Its safety profile in any animal model has never been established. Despite the lack of safety information on the compound, brorphine has been sold as a designer drug since mid-2019, initially being identified in the US Midwest, though it has since been found in 2020 in Belgium. It is related in chemical structure to compounds such as benzylfentanyl and bezitramide, though it is sufficiently structurally distinct to fall outside the formal definition of a "fentanyl analogue" in jurisdictions such as the US and New Zealand which have Markush structure controls over this family of drugs.

<span class="mw-page-title-main">Etodesnitazene</span> Chemical compound

Etodesnitazene is a benzimidazole-derived opioid analgesic drug, which was originally developed in the late 1950s alongside etonitazene and a range of related derivatives. It is many times less potent than etonitazene itself, but still 70 times more potent than morphine in animal studies. Corresponding analogues where the N,N-diethyl group is replaced by piperidine or pyrrolidine rings also retain significant activity. Etodesnitazene has been sold as a designer drug, first being identified in both Poland and Finland in March 2020.

<span class="mw-page-title-main">Etonitazepipne</span> Benzimidazole derivative

Etonitazepipne is a benzimidazole derivative with opioid effects around 100 times more potent than morphine, which has been sold over the internet as a designer drug.

<span class="mw-page-title-main">Metodesnitazene</span> Chemical compound

Metodesnitazene is a benzimidazole derivative with opioid effects, though unlike related compounds such as metonitazene and etodesnitazene which are quite potent, metodesnitazene is only around the same potency as morphine in animal studies. It is illegal in both the US and UK.

<span class="mw-page-title-main">Protonitazene</span> Chemical compound

Protonitazene is a benzimidazole derivative with potent opioid effects which has been sold over the internet as a designer drug since 2019, and has been identified in various European countries, as well as Canada, the US and Australia. It has been linked to numerous cases of drug overdose, and is a Schedule I drug in the US.

<span class="mw-page-title-main">Butonitazene</span> Chemical compound

Butonitazene is a benzimidazole derivative with opioid effects, which has been sold over the internet as a designer drug. It has relatively low potency compared to many related compounds, and has generally been encountered as a component of mixtures with other substances rather than in its pure form. However, it is still several times the potency of morphine and has been implicated in several cases of drug overdose. Butonitazene is a Schedule I drug in the US, along with several related compounds.

<span class="mw-page-title-main">N-Desethylisotonitazene</span> Chemical compound

N-Desethylisotonitazene (norisotonitazene) is a benzimidazole opioid with potent analgesic effects which has been sold as a designer drug. It was first identified in 2023 as an active metabolite of the closely related compound isotonitazene, and was found to have similar potency. It is one of the strongest benzimidazole opioids discovered, with an analgesic strength 20 times stronger than fentanyl.

<span class="mw-page-title-main">Etomethazene</span> Chemical compound

Etomethazene (5-methyldesnitroetonitazene, 5-methyl etodesnitazene, Eto) is a benzimidazole derivative with opioid effects which has been sold as a designer drug over the internet since 2022, first being definitively identified in Sweden in January 2023. It is an analogue of etonitazene where the nitro (NO2) group has been replaced by a methyl (CH3) group. While formal studies into its pharmacology have yet to be carried out, it showed far less potency than etonitazene itself. Etomethazene has an analgesic potency around 20 times that of morphine with a relatively short duration of about 120 min.

<i>N</i>-Desethyletonitazene Chemical compound

N-Desethyletonitazene is a benzimidazole derivative with potent opioid effects which has been sold as a designer drug. It is better known as an active metabolite of the related compound etonitazene, but has similar activity to the parent compound and has sometimes appeared as a drug of abuse in its own right, first being identified in New Zealand in 2024.

<span class="mw-page-title-main">Etonitazene 5-acetyl analogue</span> Chemical compound

Etonitazene 5-acetyl analogue (Etoacetazene, 5-acetyldesnitroetonitazene) is a benzimidazole derivative with opioid effects, first developed in the 1950s as part of the research that led to better-known compounds such as etonitazene. It is an analogue of etonitazene where the 5-nitro (NO2) group has been replaced by an acetyl (COCH3) group. It is described as having "reduced but still significant" potency compared to etonitazene itself. This compound was also tested as part of a series of cannabinoid receptor 2 agonists, and was found to be active though with fairly low potency of 960 nM at CB2, and negligible activity at CB1.

<span class="mw-page-title-main">Etoetonitazene</span> Chemical compound

Etoetonitazene is a benzimidazole derivative with opioid effects, first developed in the 1950s as part of the research that led to better-known compounds such as etonitazene. It is an analogue of etonitazene where the ethoxy sidechain has been extended to ethoxyethoxy. It is less potent than other benzimidazole class opioids, but is still a potent mu opioid receptor agonist with around 50x the potency of morphine, and has been sold as a designer drug since around 2022.

<span class="mw-page-title-main">Flunitazene</span> Designer drug with opioid effects

Flunitazene (Fluonitazene) is a benzimidazole derivative with opioid effects, first developed in the 1950s as part of the research that led to better-known compounds such as etonitazene. It is one of the least potent derivatives from this class to have appeared as a designer drug, with only around the same potency as morphine, but nevertheless has been sold since around 2020, and has been linked to numerous drug overdose cases.

<span class="mw-page-title-main">Ethyleneoxynitazene</span> Chemical compound

Ethyleneoxynitazene (Tetrahydrofuranitazene) is a benzimidazole derivative which has been sold as a designer drug over the internet and presumably has opioid effects. It is an analogue of etonitazene where the 4-ethoxy group attached to the benzyl ring has been cyclised round to the 3-position to form a 2,3-dihydrobenzofuran ring system. It was first reported in Estonia in February 2023, subsequently in the UK in late 2023 and in China July 1st.

References

  1. 1 2 Pergolizzi Jr J, Raffa R, LeQuang JA, Breve F, Varrassi G (2023). "Old Drugs and New Challenges: A Narrative Review of Nitazenes". Cureus. 15 (6): e40736. doi: 10.7759/cureus.40736 . ISSN   2168-8184. PMC   10361140 . PMID   37485167.
  2. ↑ Ujváry I, Christie R, Evans-Brown M, Gallegos A, Jorge R, de Morais J, et al. (April 2021). "DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles". ACS Chemical Neuroscience. 12 (7): 1072–1092. doi:10.1021/acschemneuro.1c00037. PMID   33760580. S2CID   232356192.
  3. ↑ US 2944062,Hoffman K, Hunger A,"Certain Alpha (1-diethylaminoethyl (2), Alpha Aryl Acetamides",issued 5 July 1960, assigned to Ciba Pharma Products Inc.
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  10. ↑ USpatent 2935514,Hoffman K, Hunger A,"BENZMDAZOLES (sic)",published 1960-05-03, assigned to Ciba Pharmaceutical Products Inc.
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  13. ↑ European Monitoring Centre for Drugs Drug Addiction (2020-11-13). "Report on the risk assessment of N,N-diethyl-2- 4-(1-methylethoxy)phenyl]methyl]-5-nitro-1Hbenzimidazole- 1-ethanamine (isotonitazene) in accordance with Article 5c of Regulation (EC) No 1920/2006 (as amended)". European Monitoring Centre for Drugs and Drug Addiction. Publications Office of the European Union. doi:10.2810/107576. ISBN   9789294974952 . Retrieved 9 May 2022.
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  18. ↑ Hunger A, Kebrle J, Rossi A, Hoffmann K (October 1957). "[Synthesis of analgesically active benzimidazole derivatives with basic substitutions]" [Synthesis of analgesically active benzimidazole derivatives with basic substitutions]. Experientia. 13 (10): 400–1. doi:10.1007/BF02161116. PMID   13473817. S2CID   32179439.
  19. ↑ Rossi A, Hunger A, Kebrle J, Hoffmann K (1960). "Benzimidazol-Derivate und verwandte Heterocyclen. IV. Die Kondensation von o-Phenylendiamin mit α-Aryl- und γ-Aryl-acetessigester" [Benzimidazole derivatives and related heterocycles IV. The condensation of o-phenylenediamine with α-aryl and γ-aryl-acetoacetate]. Helvetica Chimica Acta (in German). 43 (4): 1046–1056. doi:10.1002/hlca.19600430413.
  20. ↑ Rossi A, Hunger A, Kebrle J, Hoffmann K (1960). "Benzimidazol-Derivate und verwandte Heterocyclen V. Die Kondensation von o-Phenylendiamin mit aliphatischen und alicyclischen β-Ketoestern" [Benzimidazole derivatives and related heterocycles V. The condensation of o-phenylenediamine with aliphatic and alicyclic β-keto esters]. Helvetica Chimica Acta (in German). 43 (5): 1298–1313. doi:10.1002/hlca.19600430515.
  21. ↑ Hunger A, Kebrle J, Rossi A, Hoffmann K (1960). "Benzimidazol-Derivate und verwandte Heterocyclen VI. Synthese von Phenyl-[1-aminoalkyl-benzimidazolyl-(2)]-essigsäure-estern und -amiden" [Benzimidazole derivatives and related Heterocycles VI. Synthesis of phenyl-[1-aminoalkyl-benzimidazolyl-(2)]-acetic acid esters and amides]. Helvetica Chimica Acta (in German). 43 (6): 1727–1733. doi:10.1002/hlca.19600430634.
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  23. ↑ Gross F, Turrian H (October 1957). "[Benzimidazole derivatives with strong analgesic effects]" [Benzimidazole derivatives with strong analgesic effects]. Experientia. 13 (10): 401–3. doi:10.1007/BF02161117. PMID   13473818. S2CID   6824038.
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  26. ↑ Seki T, Watanabe Y (May 1969). "[Studies on 2-benzimidazolethiol derivatives. VI. Synthesis and analgesic effect of 1-(2-diethylaminoethyl)-2-(p-ethoxyphenylthio)-5-substituted benzimidazole]". Yakugaku Zasshi (in Japanese). 89 (5): 617–26. doi: 10.1248/yakushi1947.89.5_617 . PMID   5817995.
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  30. ↑ Rising imports of potent drug nitazene raises concern. Australian Federal Police, 5 May 2024
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  36. ↑ Michaelides M, et al. Fluorinated Mu-Opioid Receptor Agonists. WO 2024/196438
  37. ↑ "Fourth addendum to ACMD report on the use and harms of 2-benzyl benzimidazole ('nitazene') and piperidine benzimidazolone ('brorphine-like') opioids" (PDF). Advisory Council on the Misuse of Drugs. 5 April 2024.
  38. ↑ "Third addendum to ACMD report on the use and harms of 2-benzyl benzimidazole ('nitazene') and piperidine benzimidazolone ('brorphine-like') opioids" (PDF). Advisory Council on the Misuse of Drugs. 15 December 2023.
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