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Angiology

Volume 58, Number 1, 2007

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Thromboangiitis Obliterans (Buerger*s Disease): Searching for a Therapeutic Strategy


Kosmas I. Paraskevas, MD, FASA,** Christos D. Liapis, MD, FACS, FRCS,* Despina D. Briana, MD/ and Dimitri P. Mikhailidis, MD, FASA, FFPM, FRCPath, FRCP,* Athens, Greece; London, United Kingdom

Treatment of thromboangiitis obliterans (Buerger's disease) inciudes botii surgicai and nonsurgicai approaches, or a combination of both. A definite therapeutic approach has not yet been set. This article reviews the proposed therapeutic strategies and considers the advantages and disadvantages of each treatment. Cessation of smoking seems to be the only globally accepted therapeutic measure to prevent disease progression. A number of promising novel therapeutic strategies may prove useful for the treatment of this physically and socially mutilating disease.

Introduction
Thromboangiitis obliterans (TAO), also known as Buerger's disease, was originally described by Leo Buerger almost a century ago.^ This is an idiopathic, chronic, thrombotic, nonatherosclerotic, segmental, inflammatory disease that most commonly affects the small and medium-sized arteries, veins, and nerves of the extremities.^ Systemic manifestations of the disease with cerebral, mesenteric, coronary, mammary, or multisystem arterial involvement have additionally

Angiology 58:75-84, 2007 From "Department of Vascular Surgery, ^Athens University Medical School, Athens, Greece; and the 'Department of Clinical Biochemistry, Royal Free and University College Medical School, London, United Kingdom Correspondence: Dimitri P. Mikhailidis, MD, FFPM, FRCPath, FRCP, Department of Clinical Biochemistry, Royal Free and University College Medical School, Pond Street, London NW3 2QG, UK E-mail: mikhailidis@aol.com DOI: 10.1177/0003319706291169 2007 Sage Publications

(though exceptionally) been Although TAO has a worldwide distribution, it is more prevalent in Eastern Europe, Mediterranean, and Asian countries than in Central Europe and North America.2.9-10 Thromboangiitis obliterans principally affects young men with a history of long-term, heavy tobacco use."-12 The exact pathogenesis is still obscure, i^-i'* but smoking appears to be tightly linked: cessation leads to a more benign natural course, whereas failure to quit smoking renders any therapeutic approach unsuccessful.^2.15-16 Even 1 or 2 cigarettes a day, using smokeless tobacco (chewing tobacco or snufO, or nicotine replacement, may keep the disease active.^^"^^ So far, clinical studies have demonstrated that endothelium-dependent vasorelaxation is impaired^' and peripheral sympathetic outflow is decreased.2-2i Smoking acutely increases sympathetic drive to muscle, blood vessels, skin, and the heart,^^ and passive smoking impairs endothelium-dependent arterial and vein dilatation.^^-^"* The segmental infiltration of inflammatory cells in the vessel wall in TAO is accompanied by a thrombotic occlusion of the vessel.^-'.n-i^ The mechanism for the development of thrombotic

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occlusion is unclear. The hypothesis that a hypercoagulable state enhanced by a genetically determined mutation in a specific prothrombotic factor (prothrombin 20210A instead of prothrombin 20210G) is significantly associated with the occurrence of TAO (P = .032, odds ratio, 7.98; 95% confidence interval, 2.4-25.9) has been supported by some.^^ Other researchers believe that prothrombotic risk factors are not involved in the pathogenesis of TAO.2^ Instead, they claim that an inflammatory process in the vessel wall, triggered by heavy smoking and causing endothelial dysfunction and thrombus formation, is the primary pathomechanism.2^-2^ No definitive form of treatment has been established. Discontinuation of tobacco use seems to be the only accepted successful measure of influencing the progression of TAO."-i^'22-24.28 Indeed, cessation of smoking leads to remission of the disease and avoidance of crippling amputations. A number of therapeutic approaches have been described with varying success; however, none has succeeded in obtaining uniform acceptance.

Surgical Strategies
A few decades ago, sympathectomy, namely lumbar sympathectomy for lower extremity TAO and thoracic sympathectomy for upper extremity TAO, was widely applied as the standard surgical procedure for the treatment of TAO. Recently, however, this approach appears to have noticeably changed, with the number of surgical procedures declining or, more likely, virtually abolished.^'-^o Nakajima^i acknowledged in a review that marked improvement in clinical symptoms was accomplished in more than 60% of patients with TAO who received sjmipathectomy in his study; however, he had not performed a single surgical sjonpathectomy for the past decade. He attributed this shift to various less invasive and therefore more popular pharmacologic approaches. Sympathectomy for the treatment of TAO still has its supporters,^^"^^ but the actual role of sympathectomy in preventing amputations or treating pain has been widely questioned. Roncon-Albuquerque et aP'* tried to shed light on the controversy about the effectiveness of sympathectomy in the management of TAO. They demonstrated an impairment of sympathoadrenail function, with lower plasma catecholamines and

an altered peripheral adrenergic response to cigarette smoking. They also showed that surgical sympathectomy increases plasma concentrations of adrenalin, which is reversed after smoking. These observations suggest that surgical sympathectomy may stimulate adrenal medullary function. This may allow patients with TAO to have higher plasma adrenalin/noradrenalin ratios, with enhanced basal vasodilatation, because adrenalin has a lower vasoconstrictor effect than noradrenalin.^^ The conclusion was that sympathectomy, by promoting vasodilatation, may be useful in the management of TAO. Even better results are achieved when sympathectomy is combined with adrenalectomy.36 The usefulness of surgical sympathectomy seems to be dependent on smoking cessation.^'* Arterial reconstruction has been considered as an alternative therapeutic approach for patients diagnosed with TA0.2.3i-34,36-4o -phe long-term results of arterial reconstruction are not satisfactory, however.3^'* The diffuse segmental involvement and distal nature of the disease usually preclude surgical revascularizadon^^i^^; however, in cases of severe critical limb ischemia and if a distal target vessel actually exists, bypass surgery should be considered.^-^^'"' In this case, the bj^ass material used must be autogenous saphenous vein.2.37.38 The general rule that applies in such cases is that the more distal the arterial bypass, the lower the postoperative patency rate achieved by the revascularization procedure.^^'^^^^ Omental transfer has also been proposed as a therapeutic option for patients with TAO. The results of a stud/*^ including 50 patients with TAO who underwent omental transfer to treat rest pain, nonhealing ischemic ulcerations, or both, showed that virtually all patients had an improvement in skin temperature, and 72% had decreased rest pain. Moreover, the ulcers healed in 64% of the patients. Positive results for the efficacy of omental transfer in the treatment of TAO have also been reported by othgj-g 42,43 -pj^is approach has not been widely used, however, and thus no definite results have been obtained on its efficacy.

Nonsurgicai Strategies
Pharmacologic Strategies
Extensive research on pharmacologic alternatives for the treatment of TAO has taken place with variable success (Table I).28,44-60

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Table I.

Nonsurgicai therapeutic strategies employed for the treatment of thromboangiitis obliterans.

Study

Year 2003

Patients (n)

Method

Outcome

Matsushita et

Continuous intra-arterial infusion of urokinase (20,000 U/h) and heparin (800 U/h) for 7 days, followed by oral administration of saprogelate (serotonin antagonist, 300 mg/day) and beraprost sodium (prostaglandin 12 analog, 120 mg/day) IV regional guanethidine injection of 10 mL guanethidine in 20 mL saline (upper extremity); 20 mL guanethidine in 40 ml saline (lower extremity) A single transvenous regional block, 60 mL physiologic saline with 5 mg guanethidine, 50 mg lidocaine, 3000 IU heparin

Left leg amputation 7 months after onset of TAO due to inability of the patient to cease smoking. After cessation of smoking (after amputation), ulcers healed completely; no recurrence of ulcers or gangrene.

Olshwang et

1980

Marked relief of pain, decreased sensitivity and improved color in 2. Only slight pain relief, no change in the appearance of the extremity in 1. No pain relief for 2. Not specified for TAO but for the whole study group: 92.6%: reduction of rest pain, numbness, vasospastic attacks. 74.1%: complete disappearance of ischemic rest pain. 83.3%: complete healing of fingertip ulcerations. Relief of rest pain. Treatment of leg ulcers when smoking was discontinued (66%). Twenty-fold increase of mean claudication distance (from 36 to 762 m). 85% on iloprost: ulcer healing or ischemic pain relief vs 17% of the aspirin group. 63% on iloprost: complete pain relief vs 28% on aspirin. 35% of the iloprost group: complete ulcer healing vs 13% on aspirin. After 6 months, total relief of rest pain w/o analgesics in 49% on placebo, 63% (P = .02 vs placebo) on lowdose iloprost, and 49% (P = .604 vs placebo) on high-dose iloprost. Combined end point (alive, no major amputation, no lesion, no rest pain, no analgesics) was attained by 19% on placebo, 50% (P = .016 vs placebo) on low-dose iloprost, and 39% (P = .279 vs placebo) on high-dose Ooprost. Marked increase in linger blood flow was achieved even after thefirstseries. Complete disappearance of both fingertip ulcerations and ischemic rest pain was achieved after the end of the therapeutic protocol.

Stumpflen et al'*^

2000

Saha et

2001

12

400 mg/d cyclophosphamide IV for 7 days 100 mg/d cyclophosphamide oral for 7 weeks

Fiessinger et al''

1990

133

68 patients: 6h/day-iloprost infusion at 2.0 ng/kg/min 65 patients: 100 mg/day aspirin oral

The European TAO Study Group'*'*

1998

319

Three study groups: Oral iloprost, 100 mg, twice daily. Oral iloprost, 200 mg, twice daily, or Oral placebo, twice daily for 8 weeks oral

Paraskevas et

2005

5 sessions (1 on every 3rd day), each composed of intra-venous regional administration of 20 mg guanethidine and 100 mg lidocaine. 10 sessions (1 on every 10th day), each composed of

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Table I. (continued)

Study

Year

Patients (n)

Method intravenous regional administration of 10 mg guanethidine and 100 mg lidocaine. Eight sessions (1 on every 15th day), each composed of intravenous regional administration of 10 mg guanethidine and 100 mg lidocaine

Outcome Excellent pain relief and full restoration of both blood flow and function of the affected fingers was achieved after completion of the session series, an effect that remained unchanged 2 years after the end of the therapeutic protocol.

Hussein et aP

1993

11

Selective low-dose intra-arterial streptokinase (a 10 000 U bolus followed by 5000 units per h) 1 nicotine gum (2 mg nicotine per piece) for 20 min twice/day

Avoidance of further amputations or alteration in the level of amputation in 58.3% of the patients. Increase in skin temperature (from 23.64C to 29.89C, average values); complete healing of left big toe ulcer, disappearance of intermittent claudication. Subjective complaints were diminished in 4 out of 10 patients whereas no obvious effect was observed in the rest.There was a tendency for ankle pressure index to improve 8 weeks after treatment compared to baseline (from 0.79 0.21 to 0.85 0.18, P = .050).-^ Almost immediate pain relief. Increase of the temperature of the extremity. Complete healing of aU digital ulcerations (right thumb, index and ring fingers). Regression of ischemic pain and paresthesia, increase in skin temperature, return of normal skin color, and complete healing of trophic lesions. No disease recurrence after a mean 23.6 months follow-up. Complete healing of necrotic ulcerations on 2nd, 3rd, and 4th toes of the patient's left foot already 15 days after implantation of the SCS. Return of lower extremity distal pulse and normal color at 6 months. Remission of pain and complete healing of wounds without recurrence of ischemic lesions after 4 months of SCS therapy. Of 13 with ischemic trophic lesions, the lesions were completely healed in 7; 4 and 2 had minor and major amputations, respectively. Limb survival rate: 93.1% No new ischemic lesions appeared. Improvement of mean regional perfusion index and ankle/brachial index.

Kawabata et

1999

Rydzewski et a l "

1996

10

Sarpogrelate 100 mg 3 times a day oral

Swigris et

1999

Electrical SCS followed 1 week later by a permanent cervical epidural spinal cord stimulator

Chierichetti et

2002

SCS

Manfredini et aP=

2004

SCS

Pace et

2002

SCS

Donas et

2005

29

SCS

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Table I. (continued)

Study Isner et

Year 1998

Patients (n) 7''

Method Two intramuscular injections 4 weeks apart with 2 000 or 4 000 fig of phVECF165, at 4 selected sites in the ischemic limb

Outcome New collaterals were demonstrated angiographically in all patients. Relief of rest pain and healing of leg ulcers in 5/7 limbs. Unsuccessful therapeutic response in 2/7 limbs (below-knee amputation was required). Pain-free walking distance improved at 4 weeks (from 72.1 33.5 m to 189.3 108.9 m, P = .053 vs baseline). Maximum walking distance significantly improved at 4 weeks (from 203 95.4 m to 559 318 m, P = 0.031) and continued to improve at 24 weeks (858 305.9 m, P = .019). Ischemic ulcers improved 4 or 8 weeks after treatment. Reduced rest pain, increased claudication distance, and healing of foot ulcers in all limbs.

Ishida et

2005

Autologous peripheral blood mononuclear cell implantation

Inan et

2005

Kirschner wire placed in the medullary canal of the tibia

Note: TAO, thromboangiitis obliterans, SCS, spinal cord s stimulation; VEGF, vascular endothelial growth factor. a. The study included 28 patients with peripheral vascular disease, but only 5 had TAO. b. The study included 27 patients with critical finger ischemia, but only 4 had TAO. c. Ankle pressure index: The ratio of systolic blood pressure calculated as ankle pressure/ brachial pressure. d. Six patients (7 limbs) were included in the study. e. Of the 5 patients included in the study, 4 had TAO, 1 had arteriosclerosis obliterans. One of the TAO patients had 2 lesions treated. f. Six patients (11 limbs).

In 1980, Olshwang et al"^ used intravenous regional sympathetic blocks with guanethidine to treat 28 patients with Raynaud's disease, TAO, or other vasospastic obstructive peripheral vascular diseases of various etiologies. Guanethidine inhibits the presynaptic release of norepinephrine by displacing it from storage sites at the nerve endings and preventing its reuptake^^; it is therefore an inhibitor of norepinephrine-caused (sympathetically-mediated) vasoconstriction. They demonstrated that in patients diagnosed with TAO, the results from intravenous regional sympathetic blocks with guanethidine were not as good as in the rest of the patients. These patients benefited less from intravenous regional guanethidine block, according to both clinical picture and laboratory tests. In another study, 27 patients (4 of whom had TAO) presenting with ischemic rest pain or

ulcerations of the fingers, or both, received a single block with 5 mg of guanethidine injected in 60 mL of physiologic saline through an indwelling cannula into the clinically more affected hand under 30 min of arterial arrest.''^ Marked hyperemia, which persisted for a month, was induced in the treated limb compared with the contralateral upper limb, as indicated by the increase in finger blood flow, skin temperature, and laser-Doppler flux. Clinical outcome was also good. The authors observed that although the effects of transvenous regional guanethidine blockade in patients presenting with ischemic fingertip ulcerations were less pronounced than in those without, statistically significant increases of all evaluated parameters existed even in these most severe cases of upper extremity occlusive disease. They justified the better findings they recorded for patients diagnosed

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with TAO, compared with the results from the Olshwang et al"*"* study, on their use of a higher infusion volume (60 mL versus 20 mL) and longer duration of arterial arrest (30 minutes versus 10 minutes). Another pharmacologic agent used to treat TAO was the immunosuppressive agent cyclophosphamide. Saha et al"*^ used a combination of oral and intravenous cyclophosphamide for the treatment of TAO on the grounds of the autoimmune etiology of the disease, first proposed by Sulzberger^^ ^^d later advanced by Gulati et al,^^'^'* and also supported by independent observations of others.^5"^ Of the 6 patients with TAO and established ulcerations, only 2 healed completely, another 2 healed only partially, and the remaining 2 patients, who continued to smoke, showed no improvement. Virtually all patients noted an improvement of intermittent claudications, with the mean claudication distance increasing 20-fold, but the treatment results in already consolidated ulcers were modest. The immunosuppressive effect of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins)^^'^^ could theoretically provide the basis for future investigation on the role of statins in the treatment of TAO. A prospective, randomized, double-blind trial compared the effects of a 6-hour daily infusion of iloprost, a stable prostacyclin analog, with those of low-dose oral aspirin (100 mg/day) for 21 to 28 days."*^ Iloprost showed clear superiority compared with aspirin: 58 (85%) of 68 patients in the iloprost group were considered to be responders by an independent observer, whereas for the aspirin group, similar results were obtained for only 11 (17%) of 65 patients (P < .05). At 6 months' follow-up, 88% of the patients receiving iloprost reported improvement compared with 21% in the aspirin group. Furthermore, 6% of the iloprost group required amputation compared with 18% in the aspirin group. Other investigators have also supported the effectiveness of intravenous iloprost. ^^ Oral iloprost is not as effective as the intravenous form. In a double-blind, randomized, placebo-controlled trial'*^ with 3 equal groups of patients each assigned to either l()0 |a.g oral iloprost, 200 |i,g oral iloprost, or placebo twice daily for 8 weeks, low-dose iloprost was significantly more effective than high-dose iloprost or placebo. At the end of the 6-month follow-up period, total relief of rest pain without analgesics was attained by a significantly (P = .020) higher percentage of patients on low-dose iloprost compared with

placebo or high dose iloprost (63% versus 49% and 49%, respectively), in addition, for the end point of improved healing of the most important lesion at the end of the 6-month follow-up period, low-dose iloprost was again more effective than either high-dose iloprost or placebo at 84% (P = .007 versus placebo), 68% (P = .297 versus placebo), and 62%, respectively. The incidence of adverse effects during the 8-week treatment period was 25% higher in the high-dose iloprost group than in the low-dose group. Although the results of the low-dose oral iloprost were not as good as those obtained with intravenous iloprost,^^ the latter approach entails the need for hospitalization, a major drawback. An encouraging result was recently published by our group."*^ A patient presented with critical blood flow in the middle, ring, and little finger of his right hand owing to TAO, with ischemic ulcerations apparent in the fingertips of these 3 fingers. He had already undergone an amputation of the distal phalanx of his little finger 6 months earlier because of gangrenous necrosis. After 23 consecutive intravenous regional S5Tnpathetic blocks (Bier's blocks) with a combination of guanethidine and lidocaine, complete remission of the disease was provided. No recurrence of the disease was noted at the 2year clinical follow-up. It should be mentioned, however, that the patient had been a heavy smoker (50 cigarettes/day for more than 40 years) when he presented to our department, but he managed to reduce his daily smoking to about 10 cigarettes while on treatment and affer completion of the therapeutic protocol. A number of studies demonstrated that certain hemorheologic parameters, such as hematocrit, blood and plasma viscosity, plasma fibrinogen, and red blood cell rigidity, are altered in patients with TAO.^^^-^^ It was postulated from these findings that intraarterial thrombolytic therapy might be useful. Selective low-dose intraarterial streptokinase (a 10 000-unit bolus followed by 5000 units/h) was used in a study of 11 patients with advanced TAO who developed gangrene or ischemic pregangrenous lesions on their toes or feet, and successful avoidance of further amputations or alteration in the level of amputation was reported in slightly more than half of the patients.^ As the authors themselves pointed out, however, thrombol5^ic therapy has a deflnite role in the treatment of TAO in selected cases only. An additional aspect that deserves further investigation is whether lipid-regulating therapy.

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through its documented effect on hemorheologic parameters,^^"^'* has a role in the treatment of TAO. The documented pleiotropic actions of statin therapy^^"^^ should also be investigated for a potential beneficial role in TAO. An interesting case of successful treatment of a digital ulceration caused by TAO was reported.^^ By using one piece of nicotine gum (2 mg/piece) twice a day, an already existing ulceration of the big toe healed completely. In addition, the patient's feet remained without any other ulceration or intermittent claudication, when 2 pieces of nicotine gum were used daily without any other drugs. It must be noted, however, that in the healing of the existing digital ulceration, oral prostaglandin Ei and a serotonin blocker were used concomitantly with the nicotine chewing gum. Serotonin blockers alone have been used successfully for the treatment of TAO.'^^ These results should be considered with caution for an additional reason: the patient had smoked 5 to 20 cigarettes daily for 20 years but had stopped smoking after admission. One may therefore argue that the reported results could derive from smoking cessation alone.
Alternative Strategies

Alternative nonsurgicai, nonmedical modes of treatment have also been used (Table I). Electrical spinal cord stimulation (SCS) has been recently used for the treatment of TAO because of its analgesic effect and secondary improvement of skin microcirculation in the dermatomes being stimulated.^^ According to the gate control theory of pain, stimulation of large-diameter type A fibers at the posterior horns of the spinal cord by low-amplitude electric current inhibits simultaneous transmission of painful stimuli through the same spinal cord segment. In a similar way, inhibition of sympathetic vasoconstriction improves the peripheral microcirculation. Chierichetti et aP'* used this method to treat 3 patients with TAO. They claimed to achieve good control of painful symptoms with discontinuation of the opioid used 24 to 72 hours after initiation of SCS, increase in skin temperature, and a progressive improvement of the trophic lesions to the point of complete healing. In addition, during an average 23.6-month followup period, none of the patients presented with ischemic relapses. Even though SCS successfully deals with the neurogenic element of pain, the control of somatic pain provoked by skin

trophic lesions is the weak point of this kind of treatment. It aids in the recovery of ischemic lesions by improving skin vascularization but is ineffective in dealing with somatic pain, meaning that additional pharmacologic analgesia is necessary when lesions are present. In arterial insufflciency, SCS can decrease rest pain (Fontaine class Ili), raise skin temperature, improve claudication distance, increase transcutaneous oxygen tension in the forefoot, and aid in ulcer healing.^^'^' These reports and others^^-^^ hold implications for the use of SCS in the treatment of TAO. Isner et aP^ attempted to treat 6 patients (7 limbs) with TAO by the use of intramuscular gene transfer of naked plasmid DNA encoding for the 165 amino acid isoform of vascular endothelial growth factor (phVEGFies). Their study was based on the concept of therapeutic angiogenesis by stimulating the development of collateral arteries in peripheral and myocardial ischemia, as shown in early, preclinical animal studies.^"'3 Rest pain was relieved and necrotic ulcers healed in all but 2 limbs, which eventually required below-knee amputation. The authors concluded that treatment of TAO by intramuscular phVGFj6s gene transfer was sufficient to bring about the healing of gangrenous ulcers or toes in 4 limbs and to relieve the rest pain in all but 2 of the 7 treated limbs. Work by other independent investigators'^'*'''^ also supported the concept that intramuscular gene transfer of plasmid DNA may achieve significant improvement in patients with critical limb ischemia and TAO. Positive results have been reported in a number of recent trials after autologous bone marrow cell transplantation (mononuclear cells, platelets, and endothelial progenitor cells)'^''^ for the treatment of peripheral arterial disease and critical limb ischemia, although not specifically for TAO. Similar results were reported after granulocytecolony stimulating factor-induced mobilization of hematopoietic stem cells, as well as endothelial progenitor cells from bone marrow to peripheral blood, and implantation of autologous peripheral blood mononuclear cells in the ischemic limb muscles of 5 patients diagnosed with TAO and 1 patient with arteriosclerosis obliterans.^^ In another report, an intrameduUary Kirschner wire placed in the medullary canal of the tibial bone stimulated angiogenesis in patients with TAO.^ These data suggest that therapeutic angiogenesis could be a novel therapeutic tool for the management of TAO.

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Conclusions
The tendency is growing toward replacement of the already established surgical techniques with less aggressive and perhaps more successful nonsurgicai alternatives. Nonsurgicai treatments for the treatment of TAO seem to be more advantageous than surgical procedures; however, this is not a universally accepted view. Therapeutic angiogenesis, although still at an early stage, is potentially promising. The only widely accepted therapeutic measure for TAO seems to be smoking cessation. The need for the establishment of a definitive mode of coping with this psychologically and socially mutilating disease'*" is demanding. More research is urgently needed.

REFERENCES
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