Thorax 1995;50:1080-1086

Comparative effects of plasma exchange andpyridostigmine on respiratory muscle strengthand breathing pattern in patients withmyasthenia gravis

Patrizio Goti, Alessandro Spinelli, Giampiero Marconi, Roberto Duranti,Francesco Gigliotti, Assunta Pizzi, Giorgio Scano

Section of PulmonaryMedicine,Department ofInternal Medicine,Clinica Medica IIIA SpinelliR DurantiG Scano

Department ofNeurology andPsychiatryG Marconi

University of Florence,Italy

Pro Juventute Don C.Gnocchi Foundation,Pozzolatico, Florence,ItalyP GotiF GigliottiA Pizzi

Reprint requests to:Dr G Scano, Istituto diClinica Medica III,University of Florence, VialeMorgagni 85, 50134Florence, Italy.Received 31 October 1994Returned to authors31 January 1995Revised version received21 March 1995Accepted for publication16 June 1995

AbstractBackground- Pyridostigmine, an acetyl-cholinesterase antagonist, is useful in im-proving respiratory function in patientswith myasthenia gravis. More recently,plasma exchange has been employed inmyasthenia gravis because it acts pre-sumably by removal of circulating anti-bodies against acetylcholine receptors.Surprisingly, comparative data on theeffects of pyridostigmine and plasmaexchange on lung volumes, respiratorymuscle strength, and ventilatory controlsystem in patients with myasthenia gravisare lacking.Methods - Nine consecutive patients withgrade Ilb myasthenia gravis were studiedunder control conditions and after a thera-peutic dose ofpyridostigmine. In a secondstudy the patients were re-evaluated a fewdays after a cycle of plasma exchange,before taking pyridostigmine. In eachsubject pulmonary volumes, inspiratory(MIP) and expiratory (MEP) muscle force,and respiratory muscle strength, cal-culated as average MIP and MEP as per-centages of their predicted values, weremeasured. The ventilatory control systemwas evaluated in terms of volume (tidalvolume, VT) and time (inspiratory time,TI, and total time, TTOT) components ofthe respiratory cycle. Mean inspiratoryflow (VT/TI) - that is, the "driving" - andTI/TToT - that is, the "timing" - com-ponents ofventilation were also measured.Results - In each patient treatment re-lieved weakness and tiredness, and dys-pnoea grade was reduced with plasmaexchange. Following treatment, vital cap-acity (VC) increased on average by 9-7%with pyridostigmiine and by 14% withplasma exchange, and MIP increased by18% and 26%, respectively. In addition,with plasma exchange but not with pyrido-stigmine forced expiratory volume in onesecond (FEV1) increased by 16% and MEPincreased by 24-5%, while functional re-sidual capacity (FRC) decreased a little(6-8%). The change in respiratory musclestrength was related to change in VC (r2 =0.48). With plasma exchange, VT increasedby 18*6% and VT/TI increased by 13-5%,while neither TI nor TIrrTOT changed.

Conclusions - Plasma exchange can beused in patients with myasthenia graviswhen symptoms are not adequately con-trolled by anticholinesterase agents.Plasma exchange increases respiratorymuscle force and tidal volume due tochanges in "driving" but not "timing" ofthe respiratory cycle.(Thorax 1995;50:1080-1086)

Keywords: pyridostigmine, plasma exchange, myas-thenia gravis, respiratory muscle strength.

Plasma exchange is regarded as an establishedmethod for treating patients with myastheniagravis when other treatments have been in-effective.1` It can also be used to reduce sur-gical complications of thymectomy. Underthese circumstances plasma exchange isthought to act by reducing circulating anti-bodies against the acetylcholine receptor(AChR),l the plasma factor directly concernedin producing the disorders of neuromusculartransmission in the acquired form of thedisease.45

Several studies have reported the effects ofpyridostigmine, a cholinesterase inhibitor, onrespiratory muscle function in patients withmyasthenia gravis.8 Whilst hypoventilationand CO, retention are recognised con-sequences from respiratory muscle weakness,there are few studies which evaluate the controlof breathing in patients with chronically stablemyasthenia gravis.8"- Furthermore, there areno comparative data on the effects of pyrido-stigmine and plasma exchange on respiratorymuscle strength and ventilatory control inpatients with myasthenia gravis. We have there-fore undertaken an uncontrolled study to pro-vide an insight into these aspects of treatmentof myasthenia gravis

MethodsSUBJECTSNine consecutive patients (three men) aged22-68 years with moderate generalised my-asthenia gravis were studied. Informed consentwas given by each patient and the study wasapproved by the local ethics committee. Diag-nosis of myasthenia gravis was defined on thebasis of a clinical history of tiredness, weaknessof the skeletal muscles, a decremental responseto repetitive motor nerve stimulation test, and

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Table 1 Anthropometric and clinical data ofpatients with grade IIb myasthenia gravis

Patients Age (yrs) Sex Antibodies Duration of both disease STD Thymectomyand treatment (yrs) (mg x 10')

AchR SM

C PE C PE

1 68 M 20 8 1:160 <1:80 6 21 6 Yes*2 63 M 54 42 1:160 <1:80 8 28-8 Yes*3 65 F 85 52 - - 4 21-6 No4 57 M 44 25 1:160 <1:80 1 10-8 Yes*5 22 F 35 15 - - 1 10-8 Yes6 30 F 18 7 - - 2 14-4 Yes7 33 F 15 10 - - 4 21-6 Yes8 38 F 28 13 - - 1 10-8 Yes9 30 F 64 29 - - 5 27-0 Yes

AchR= acetylcholine receptor; SM= skeletal muscle; C = control; PE = plasma exchange; STD = steroid total dose (daily dose x 180days x years).* Thymoma.

a positive edrophonium chloride (Tensilon)test."2 Acetycholine receptor antibodies wereavailable in all patients and skeletal muscleantibodies in three; all patients belonged to theIIb grade of myasthenia gravis according toOsserman's classification'2 13: I, ocular my-asthenia; Ila, mild generalised myasthenia; IIb,moderate generalised myasthenia; III, acutesevere myasthenia; IV, late severe myasthenia.Patients had normal routine chest radiographs.All but one (patient no. 3) had undergone athymectomy which, in three cases (nos 1, 2,and 4), was due to thymoma. Patients werebeing treated with oral anticholinesterasetherapy (pyridostigmine, 60 mg three or fourtimes daily) and alternate day prednisone(20-60 mg), which was insufficient to controlsymptoms. No patients fulfilled the diagnosticcriteria for asthma, chronic bronchitis or em-physema as suggested by the American Thor-acic Society.'4 All but three patients (nos 2, 8,and 9) were non-smokers.At the time of the study they were dyspnoeic

with grade II (walking at ordinary pace on thelevel) to III (walking at their own pace on thelevel) dyspnoea.'5 No patient was consideredto be undernourished and mean (SD) bodyweight, expressed as percentage of idealweight,'6 was 95(8)%. The clinical data of thepatients are summarised in table 1.

MEASUREMENTSRoutine spirometric tests were performed whenseated as previously described.'7 The normalvalues for lung volumes were those proposedby the European Community for Coal andSteel.'8 Maximal static inspiratory (MIP) andexpiratory (MEP) pressures were measuredusing a differential pressure transducer (Sta-tham SC 1001; Hato Rey, Puerto Rico). Thesubject, comfortably seated and wearing anoseclip, performed maximal respiratory effortsat residual volume (RV) (for MIP) and at totallung capacity (TLC) (for MEP) against anobstructed mouthpiece with a small leak (in-ternal diameter 0-6 mm) to minimise oral pres-sure artefacts. The manoeuvres were repeateduntil three measurements sustained for at leastone second and with less than 5% variabilitywere recorded. The highest value obtained wasused for analysis. MIP and MEP were ex-pressed both in cm H20 and as percentage ofpredicted value (%pred). The predicted valuesfor MIP and MEP were those proposed byBlack and Hyatt.'9

After baseline routine testing while breathingroom air the ventilatory pattern was evaluated.The subjects, wearing a noseclip, were put ina comfortable supine position breathingthrough a mouthpiece on a circuit where theinspiratory and expiratory lines were separatedby a one-way valve (Hans-Rudolph, KansasCity, Missouri, USA). Airflow was measuredwith a Fleisch type 3 pneumotachograph andthe flow signal was integrated into the volume.From the spirogram the following breath-by-breath time and volume components of therespiratory cycle were derived: inspiratory time(TI), expiratory time (TE), total time of therespiratory cycle (TTOT), and tidal volume(VT). Mean inspiratory flow (VT/TI) "driving",duty cycle (Ti/TToT) "timing", respiratory fre-quency (Rf= 1/TTOT x 60), and instantaneousventilation (VE =VT x RJ) were also calculated.Expired CO2 (Pco2) was sampled continuouslyat the mouth by an infrared CO2 meter. Thevalues for dead space and resistance of thesystem up to a flow of 4 1/s were 178 ml and0 92 cm H20/l/s, respectively. Details of themethods have been described previously.820The output ofthe CO2 meter, the flow signal,

and the integrated flow signal were recordedcontinuously on a multichannel chart recorder.After a 10 minute adaptation period the base-line evaluation was started.

Ventilatory parameters were calculated fromthe data averaged from the breaths recordedover 10 minutes.

PLASMAPHERESISPlasma exchange was performed using a dis-continuous flux cellular separator (Didecomodel Progress BT 790A) and by mono-usecell apheresis (Dideco model BT 225). Per-fusion of plasma substitutes consisted of: (a)750-1000 ml saline, (b) 500 ml 10% colloidalsolution of low molecular weight dextran insaline, (c) three Baxter electrolytic rehydratingSolution (300 ml) plus 5000 IU heparin, and(d) four 50 ml vials of 20% human albuminadded to 750 ml saline. According to theAmerican Society for Apheresis2' plasma vol-ume removal was 5% body weight. Each patienthad 5-9 courses of plasma exchange.

DATA ANALYSISStatistical analysis was performed by two wayanalysis of the variance and intergroup com-

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Table 2 Mean (SD) baseline pulmonary function data under control conditions (C), after pyridistogmineadministration (P), and plasma exchange (PE) in patients with myasthenia gravis

VC RFC RV TLC FEV, FEV,I/VC MIP MEP(SR) (SR) (SR) (SR) (SR) (Oo) (%pred) (%pred)

C -1 46 1-21 1-74 -0-14 -1-52 77-7 56-2 38-2(1-88) (1-26) (1-96) (1-17) (1-65) (16-3) (19-5) (18-8)

P -0-80 1-23 1-14 -0-25 -0-96 76-8 68-5 45-2(1-72) (1-46) (2 03) (1-18) (1-54) (12-7) (21-2) (16-2)

PE -0 35 0-775 0-77 0 10 -0 47 78-4 75-8 50-6(1 56) (1-26) (1-79) (1-22) (1-43) (13-6) (21 3) (16-5)

Analysis of varianceF 12-71 6-99 4 79 2-21 10 43 0-28 30 35 4 013p 0 0005 0-01 0-025 NS 0-002 0-76 0-0001 0 05

Bonferroni test (p values)P v C <0 05 NS NS NS NS NS <0.05 NSPE v C <0 05 <0 05 <0 05 NS <0 05 NS <0 05 <0 05PE v P NS <0 05 NS NS NS NS <0 05 NS

SR=standardised residuals; VC=vital capacity; FRC=functional residual capacity; RV=residual volume; TLC=total lungcapacity; FEV, = forced expiratory volume in one second; MIP = maximal inspiratory pressure; MEP = maximal expiratory pressure.

parisons by the Bonferroni test. Spirometricvalues have been reported as standardised re-siduals22 obtained by dividing the absolute re-siduals by the residual standard deviationstaken from the regression equation.'8 A p valueof <0 05 was considered to be significant.

PROTOCOLAll treatment was withdrawn from the patientsat least 12 hours before the study. Baselinelung function, MIP, MEP, and ventilatory pat-tern were measured at approximately 09.00hours. Patients were allowed to rest betweentests to avoid the effect of fatigue.

Study I: The patient was fasted and a singleoral dose (120 mg) ofpyridostigmine was given.Functional evaluation was repeated whenpatients felt better (less difficulty with chewingand swallowing, decrease in facial and limbmuscle weakness), approximately 30 minutesafter administration of the drug.

Study II: One to two days after the first studypatients underwent the first of 5-9 courses ofplasma exchange. Treatment was performedover 18-27 days, and 2-4 days after completionof the plasma exchange cycle dyspnoea grade,spirometry, respiratory muscle strength, andthe pattern of breathing were re-evaluated atthe same time in the morning as in the firststudy.

Study III: Four patients who carried outthe first study on an off-steroid day were re-

evaluated on either the on-steroid or off-steroidday 30 minutes and two hours after a dose of120 mg pyridostigmine.

ResultsBaseline pulmonary function data and maximalinspiratory and expiratory pressures for patientsare summarised in table 2 and fig 1. Somepatients exhibited a low vital capacity (VC) (nos1-3, 5, 6), while functional residual capacity(FRC) (nos 1, 3, 9) and residual volume (RV)(nos 1, 3, 5, 6) were mild to moderately in-creased in some patients. The ratio ofthe forcedexpiratory volume in one second (FEVy) to VCwas low in the three patients with a smokinghistory (nos 1, 2, 4). MEP was slightly tomoderately reduced in all patients and MIP inall but two (nos 7 and 8).The characteristics of the breathing pattern

in the patients were compared with those of a

group of 11 age-matched normal subjects (ninewomen of mean (SD) age 42-1 (16.1) years(range 20-67)) as shown in table 3 and fig 2.As a group the patients exhibited a more rapidand shallow breathing pattern: smaller VT, nand greater Rf and VTM. All these differenceswere significant (p<0-025 to <0 005). In con-trast, ventilation (VE) was similar in the patientsand controls.As shown in table 2 and fig 1, pyridostigmine

and plasma exchange both resulted in a sig-

Table 3 Breathing pattern under control conditions (C), after pyridostigmine (P) administration, and plasma exchange(PE) in patients with myasthenia gravis. Values are mean (SD)

VE VT Ti Rf VT/TI TI/TTOT(lImin) (7) (s) (breaths/min) (Ifs)

C 9-65 0-57 1-3 17-63 0 45 0 37(1-5) (0-1) (0 2) (4 2) (0-1) (0 06)

P 9 94 0-62 1-34 16-7 0 47 0-36(2-2) (0-14) (0 3) (4 6) (0-12) (0-06)

PE 11-2 0 7 1-4 16-1 0-52 0 37(2 7) (0-1) (0 3) (3-8) (0-1) (0 05)

Analysis of varianceF 3-16 10-14 1-05 1 99 8-61 0-14p NS 0-002 NS NS 0 005 NS

Bonferroni test (p values)P v C NS NS NS NS NS NSPE v C NS <0 05 NS NS <0 05 NSPE v P NS <0 05 NS NS <0 05 NS

VE=minute ventilation; VT=tidal volume; Ti=inspiratory time; Rf=respiratory frequency; VT/T = mean inspiratory flow;TI/TToT = timing.

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401-

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C

130 r

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Figure 1 Individual change in vital capacity (VC), forced expiratory volume in one second (FEVE), maximalinspiratory pressure (MIP), and maximal expiratory pressure (MEP) after pyridostigmine (P) and plasma exchange(PE) in the nine patients with myasthenia gravis. C= control.

nificant increase in VC (p<005 for both treat-ments). Plasma exchange resulted in a mildbut significant decrease in FRC compared withboth control and pyridostigmine (p<0 05 forboth comparisons). RV decreased and FEV1increased with plasma exchange but not withpyridostigmine (p<0 05 for both variables).Both treatments resulted in a significant in-crease in MIP (p<0.05 for both), but the in-crease in MIP with plasma exchange wasgreater than that with pyridostigmine (p<0 05);in contrast, MEP increased only with plasmaexchange (p<0 05).Change in respiratory muscle strength, cal-

culated as the average % predicted MIP andMEP," significantly related to change in VC(r=O0696, p=O0001), but neither related tochange in FRC nor to the duration of thedisease. For each subject the calculated totaldose of steroid (daily dose x 180 days x years,table 1) did not relate to baseline MIP orrespiratory muscle strength, nor to im-provement in MIP or respiratory musclestrength with pyridostigmine or plasma ex-

change.In terms of breathing pattern (table 3 and

fig 2) VT and VTM increased with plasmaexchange compared with both the control andpyridostigmine groups (p<0O05 for all com-parisons). In contrast, T/TTOT did not changewith either treatment.

In each patient treatment relieved weaknessand tiredness. In particular, with plasma ex-

change the improvement began within a fewdays of initiating exchange and continued forsome days after the cycle ceased; dyspnoeagrade lessened from III to II in some patientsand from II to I (hurrying on a level or walkingup a slight hill) in the others. Autoantibodylevels always changed after plasma exchange(table 1).

In the third study the two hour increases inrespiratory muscle strength (fig 3), VC, FEVI,and breathing pattern did not consistently differcompared with 30 minute increases recordedeither on the on-steroid or off-steroid day.

DiscussionWe have shown that both pyridostigmine andplasma exchange improve symptoms and re-

spiratory function in a group of patients withgrade IIb myasthenia gravis. There were in-creases in static and dynamic lung volumes andrespiratory muscle strength for both agents, butonly plasma exchange led to changes in tidalvolume and mean inspiratory flow, suggestingthat this modality oftreatment affects the "driv-ing" and not the "timing" of the respiratorycycle.We have found low values for VC and high

values for RV in our patients with myasthenia

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gravis which has been reported before,6-824 andmay be a reflection of decreased musclestrength.924 However, we found that the in-crease in respiratory muscle strength with treat-ment accounted for about 50% ofthe variabilityin the increase in VC. This finding, togetherwith previous data from patients with mis-cellaneous myopathies,23 25 suggests that ab-normal muscle mechanics is not the sole reasonfor reduced VC in patients with myastheniagravis. In our studyFRC decreased with plasmaexchange but was unchanged by pyrido-stigmine. It has been shown that FRC was

not changed by orally administered pyrido-stigmine,' but did increase with injected drug.6

FRC is determined by the balance betweenlung and chest wall forces, so the observed fallinFRC by plasma exchange could have resultedfrom an increased elastic recoil of the lung, a

decrease in the outward recoil of the chest wall,or a combination of the two.25 We do not havedata on elastic recoil of the lung to allow us toestablish which factor was dominant in low-ering FRC in our subjects. The fall in FRC withplasma exchange would facilitate an increase inMIP, but in our data we did not find anysignificant relationship between change in FRCand change in MIP.

It could be argued that examination of re-

spiratory mechanics only 30 minutes after

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Plasma exchange and pynidostigmine in myasthenia gravis

pyridostigmine administration is too early topermit maximal absorption from the gastro-intestinal tract and action at the neuromuscularjunction. Furthermore, the criteria for assessingbenefit from oral pyridostigmine in patientswith myasthenia gravis often relies solely on apatient's subjective response with improvementin chewing, swallowing, or less ocular, facial orlimb weakness. We have found that two hoursafter oral administration of 120 mg pyrido-stigmine the changes in lung volumes did notsubstantially differ from the changes after 30minutes, whether recorded on the day whenon or off corticosteroids. This finding agreeswith the data of Shale et al.26 In terms ofrespiratory muscle strength, after the initialincrease of 22% and 35% from control in MIPand MEP, respectively, these parameters didnot increase any further, consistent with theobservations of Rindgqvist and Rindgqvist,24 inwhose study the maximum increase in MIPand MEP after neostigmine injection was 17%and 15% predicted respectively. Similarly, inthe study by Mier-Jedrzejowicz et al7 MIPincreased by a mean of 37% and MEP by amean of 28% after administration of intra-venous edrophonium.The low MIP and MEP values found in our

patients are likely to reflect respiratory muscleweakness - that is, the failure to generate force.In patients with myasthenia gravis inspiratorymuscle weakness might depend on the defect inneuromuscular transmission and corticosteroidmyopathy which is a well known adverse effectfrom corticosteroid treatment.2728 There is con-siderable evidence that abnormalities at theneuromuscular junction are the major problemin myasthenia gravis. In this context theremoval of AChR antibodies with plasma ex-change' could account, in part, for the increasein respiratory muscle strength. The increase inMIP with pyridostigmine will in part be dueto the fact that anticholinesterase antagonistsincrease both the action potential and force ofskeletal muscle.30 With respect to the effect ofcorticosteroids, these may reduce respiratorymuscle function in animals and man.20272832 Inparticular, they may affect striated muscles (IIbfibre atrophy) including respiratory musclestructure and function.2732 However, we werenot able to find any relation between the totaldose of corticosteroid and baseline respiratorymuscle strength, or its increase with therapy.It is therefore unlikely that long term corti-costeroid treatment played a part in the de-crease in respiratory muscle strength notedbefore and after treatment. Our finding of agreater decrease in MEP than in MIP agreeswith data from patients with neuromusculardisorders.2333 There are no data available whichcompare the histological features of the dia-phragm and expiratory muscles in patients withmyasthenia gravis to help to explain this ob-servation.

Because patients with myasthenia gravis varyin the time of their optimal strength with doseregimen, each patient should be studied oneither their day on or off steroid. The resultsfrom our third study showed that changes inpulmonary volumes and respiratory muscle

strength were indifferent to the corticosteroidregimen, and this argues against a possibleundesirable influence on our results by thefact that our patients received alternate daycorticosteroid therapy. In addition, our ob-servation that the response to pyridostigminedid not differ between days on and off steroidsupports this as a safe and satisfactory doseregimen for patients with myasthenia gravis.Our patients had a rapid and shallow breath-

ing pattern - that is, the respiratory centraloutput was modulated via shorter inspiratorytime (Tm) into a tachypnoeic pattern of breath-ing and smaller VT. This more rapid andshallow breathing is similar to that observedin patients with several neuromuscular dis-orders8-13435 including myasthenic myopathy29with chronic934 or acute'01' ventilatory failure.In neuromuscular disorders either afferent in-formation from weak respiratory muscles3637and stiffened rib cage,34 or vagal afferent in-formation from the lung,3435 have been thoughtto act on the central inspiratory controller toterminate inspiration. The observation that Tilay unchanged with treatment suggests thatneither pyridostigmine nor plasma exchangewere able to modify factors which act on thecentral inspiratory controller to terminate in-spiration. Tidal volume (VT) increased withplasma exchange but not with pyridostigmine.There is some evidence that in patients withmyasthenia gravis pyridostigmine is able to in-crease VT during some experimental conditionswhich are suspected to increase tiredness andweakness of the respiratory muscles - for ex-ample, exogenous CO2 stimulation - but notduring quiet breathing.8 The reason whyplasma exchange was able to increase VT inspontaneously breathing patients is likely to becomplex. Rochesteri8 has recently hypothesisedthat, in order to decrease the dyspnoea sen-sation, patients with muscle weakness decreasethe ratio of the inspiratory pressure for a givenbreath (Pbr) to the maximal inspiratory pres-sure (MIP), thereby decreasing VT. Our datashowing a lower dyspnoea grade and an in-creased MIP are consistent with the possibilitythat plasma exchange brings about a greaterPbr/MIP ratio promoting, as reported, a greaterVT.

In many respiratory disorders the inspiratorydrive has commonly been assessed in terms ofboth VT/TI and mouth occlusion pressure,39 butin patients with respiratory muscle weaknesseither VT/TI or mouth occlusion pressurecan underestimate the effective inspiratorydrive.3536 Thus, the observation in patients ofa higher VT/TI is not unlikely to reflect a normalor even increased neural drive to the inspiratorymuscles. The reasons for this higher drive inpatients with myasthenia gravis8 and otherneuromuscular disorders have been providedelsewhere.35-3 "Driving" (VT/T) but not "tim-ing" (TI/TToT) was found to increase withplasma exchange. Based on the equation39

VE =VT x Rf= VT/T x TI/TTOT,the increase in VT and VTM is the mechanismwhereby VE may be maintained or may in-crease.

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We conclude that plasma exchange can beused in patients with myasthenia gravis whosesymptoms are not completely controlled byanticholinesterase agents, and that plasma ex-

change increases respiratory muscle force andtidal volume by a change in the "driving" butnot the "timing" of the respiratory cycle.

Supported by grants from the Ministero dell'Universita e dellaRicera Scientifica e Tecnologica of Italy.

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