Thorax: first published as 10.1136/thx.39.2.86 on 1 February 1984. Downloaded from

Thorax 1984;39:86-92

Effect of inspiratory flow rate on bronchomotor tone in normal and asthmatic subjects

W HIDA, M ARAI, C SHINDOH, Y-N LIU, H SASAKI, T TAKISHIMA From the First Department ofInternal Medicine, Tohoku University School of Medicine, Sendai, Japan

ABSTRACT The effect of the inspiratory flow rate during deep inspiration on the regulation of bronchomotor tone was studied in nine normal and 22 asthmatic subjects. Changes in bronchial tone were assessed by respiratory resistance measured by an oscillation method. In normal subjects with induced by methacholine a rapid deep inspiration reduced respiratory resistance more than a slow deep inspiration. Asthmatic subjects with spontaneous airway narrowing showed an increase in respiratory resistance after deep inspiration that was greater after rapid than after slow deep inspiration. On the other hand, in asthmatics with methacholine induced bronchoconstriction, bronchodilatation occurred after deep inspiration and this was also greater after rapid than after slow deep inspiration. Lignocaine attenuated both bronchoconstriction and bronchodilatation induced by both slow and rapid deep inspiration. These results suggest that the effects of deep inspiration are mediated at least in part via receptors in the airways. It is suggested that in asthmatic patients with spontaneous broncho- constriction irritant receptor activity will be increased in proportion to the speed of inspiration. After methacholine induced bronchoconstriction stretch receptor activity is likely to behave in a similar fashion, leading to an opposite effect. http://thorax.bmj.com/ A deep inspiration has been reported to produce a carbachol induced bronchoconstriction, and they transient decrease in airway calibre in some - suggested that this might have been due to greater tic subjects.' 2 In contrast, in the presence of phar- stimulation of stretch receptors at higher flows. macologically induced bronchoconstriction a deep The inspiratory flow has not been controlled in inspiration produces bronchodilatation in most previous studies reporting bronchoconstriction asthmatice and normal4 subjects. The reason for induced by deep inspiration.' 2 We therefore these divergent effects of deep inspiration on bron- examined whether the flow rate during a deep inspi- chomotor tone with and without drug induced ration affects bronchomotor tone in asthmatic bronchoconstriction is unclear. Deep inspiration patients with drug induced bronchoconstriction and on October 2, 2021 by guest. Protected copyright. might stimulate different vagal sensory receptors in with spontaneous bronchomotor tone. In addition, these different circumstances: in those with artifi- we examined the effects of rate of deep inspiration in cially induced bronchoconstriction deep inspiration asthmatic and normal subjects after pretreatment might stimulate stretch receptors, which induce with lignocaine, which is known to block both irrit- bronchodilatation5; while in asthmatics without pro- ant and stretch receptors.8 We also examined voked bronchoconstriction deep inspiration might whether any bronchoconstrictor effect of the speed activate irritant receptors, inducing broncho- of inspiratory flow was related to the degree of air- constriction.6 Recently, Beaupre and Orehek' way hypersensitivity as assessed by sensitivity to observed that a fast inspiratory flow rate induced methacholine. more bronchodilatation than after inspiration with a slow inspiratory flow rate in asthmatic subjects with Methods We studied nine normal men (mean age 28-8 (SEM Address for reprint requests: Dr Tamotsu Takishima, First 1.7) years) and 22 patients with asthma (16 men and Department of Internal Medicine, Tohoku University School of six women, mean age 38-8 (3.4) years) who were Medicine, Sendai, Japan 980. diagnosed on clinical and functional criteria.9 None Accepted I November 1983 was having long term steroid treatment. All were 86 Thorax: first published as 10.1136/thx.39.2.86 on 1 February 1984. Downloaded from

Inspiratory flow rate and bronchomotor tone in normal and asthmatic subjects 87 symptomless at the time of study, and no medication analysis. Then during tidal each normal was taken for at least 24 hours before the study. subject continuously inhaled an aerosol of a single Initially the (VC) and the forced concentration of methacholine (6.25 mg/ml) for expiratory volume in one second (FEV,) were about six minutes until the Rrs was twice the initial measured with a 13*5 litre Benedict-Roth spirome- value. After inhalation of methacholine FRC usually ter. Predicted values of VC were obtained from the increased by 0S4-07 1. Rrs after slow and rapid deep data of Cotes.'0 About one hour later the effects of inspiration was then measured again as described deep inspiration were examined with the subject above. seated in a volume displacement body plethysmo- In the asthmatic subjects the effects of slow and graph"; the respiratory resistance (Rrs) was meas- rapid deep inspiration on baseline Rrs were studied ured by the oscillation technique,'2 while the volume in the same way as in the normal subjects. In 13 of change within the plethysmograph was monitored the 22 asthmatic subjects, the studies were repeated by a Krogh spirometer and Sanborn linear trans- after methacholine (6.25 mg/ml) had been inhaled ducer. A sine wave of frequency 3 Hz was generated for about one minute-that is, until there had been a at the mouth by a loudspeaker box system.'2 The twofold increase in Rrs. This increased FRC by mouth pressure relative to ambient pressure was 0-5-0 8 litre. measured with a differential pressure transducer To examine the contribution of airway sensory (Validyne, MP45 ± 50 cm H20) and air flow at the receptors to the effects of different rates of inspirat- mouth (V) with a Fleisch pneumotachograph and ory flow, studies were also performed (after the air- differential transducer (Validyne, MP45 ± 5 cm ways had been anaesthetised) in four normal sub- H20). The calculation of respiratory resistance from jects with methacholine induced broncho- Pao and V was continuously performed by an constriction and four asthmatic subjects who had analogue computer using the method of Hyatt et transient bronchoconstriction after deep inspira- al.'3 To deliver an aerosol of a bronchoconstrictor tion.8 An aerosol of 4% lignocaine was administered or , two Vaponephrin nebulisers to these subjects with the nebuliser described above (USV Pharmaceutical Corporation) that delivered over a 15 minute period during tidal breathing with 0-15 ml of solution per minute were connected bet- continuous monitoring of Rrs, which showed that ween the mouthpiece and pneumotachograph. A lignocaine itself had no measurable effect. At the constant bias flow of 0-4 1 s-' was introduced bet- end of the measurement the subject inhaled five

ween the mouthpiece and the nebuliser to minimise deep breaths of an aerosol of 10% citric acid and the http://thorax.bmj.com/ ventilation. Mouth flow, mouth pressure, absence of cough confirmed the adequacy of airway volume change, and respiratory resistance were anaesthesia.'4 recorded on a four channel direct writing recorder In additional experiments 12 of the 22 asthmatic system (Sanei, Japan). subjects had a methacholine provocation on a sepa- For assessment of the effect of flow rate during rate occasion three or four days later. Nine in this deep inspiration in normal subjects, the protocol group belonged to the group in which the flow was as follows. After functional residual capacity effects of deep inspiration had been studied after (FRC) became steady the subject inspired fully from methacholine induced bronchoconstriction as FRC to total capacity (TLC) and expired again described above. Methacholine provocation tests in on October 2, 2021 by guest. Protected copyright. to FRC with either a slow deep inspiration (SDI, these additional studies were performed by a previ- mean flow 0-22 (SEM 0.02) 1 s-') or a rapid deep ously reported technique,'5 which allows construc- inspiration (RDI, mean flow 3-62 (0-22) 1 s-'). The tion of dose response culves of Rrs during the con- flow during expiration from TLC to FRC was com- tinuous inhalation of methacholine in stepwise parable to that during inspiration with each man- incremental concentrations from 0-049 to 25-0 oeuvre. Slow and rapid deep inspirations were per- mg/ml. Rrs was again measured by the oscillation formed in random order. FRC values before and method as described above. From the dose response after each deep inspiration were within 0-2 1 of each curve we obtained the cumulative dose of other. Respiratory resistance was measured con- methacholine (Dmin) required to initiate a decrease tinuously for at least two minutes before each man- in respiratory conductance (Grs, reciprocal of oeuvre and for five minutes afterwards. Further respiratory resistance). Dmin was used as the index deep inspirations were performed at intervals of of bronchial sensitivity and expressed in units, as in about 10 minutes, when respiratory resistance had the work of Chai et al'6-that is, one unit represents returned to its baseline value before deep inspira- the inhalation for one minute of an aerosol of 1-0 tion. The effects of slow and rapid deep inspiration mUml during tidal breathing.'5 We then looked at were each examined two or three times, and average the effects of slow and rapid deep inspiration on values of respiratory resistance were used for respiratory resistance without drug induced Thorax: first published as 10.1136/thx.39.2.86 on 1 February 1984. Downloaded from

88 Hida, Arai, Shindoh, Liu, Sasaki, Takishima Pulmonary function in normal and asthmatic subjects (means with SEM in parentheses) No ofsubjects VC (% predicted) FEV,/VC % Rrs (SD) (SD) (cm H20 1 s) Normal 9 107.9 (5.5) 87.3 (1-2) 2-58 (0-18) Bronchial asthma 22 103-8 (2-3) 72-2 (3-0) 3-42 (0-15) p NS < 0-01 < 0.01 VC-vital capacity; FEV,-forced expiratory volume in one second; Rrs-respiratory resistance; NS-not significant.

Normal respiratory resistance after deep inspiration in the A normal subjects. Under baseline conditions (fig 1A) all values of respiratory resistance were within 20% r of the control values, but respiratory resistance after 0 rapid deep inspiration decreased significantly com- pared with the corresponding values after slow deep inspiration in the first 10 seconds (paired t test, p < 0.05). There were no differences between the values at 20 and at 180 seconds after the deep inspiration. B In contrast, the greater respiratory resistance (max- imum values 5-08 (0.36) cm H20 1-' s) after methacholine inhalation fell immediately after deep inspiration, with a gradual return towards control 0A levels within about 80 and 150 seconds of slow and rapid deep inspiration respectively (fig. 1B). The Ux mean maximal reduction of respiratory resistance

* RDI was 20% and 42% at 5 seconds after slow and rapid o SDI deep inspiration, and the reduction of respiratory resistance after rapid deep inspiration was Fig 1 Effects ofslow deep inspiration (SDI) (0) and rapid significantly greater than after slow deep inspiration deep inspiration (RDI) (a) on change in respiratory (analysis of variance, p < 0.05). http://thorax.bmj.com/ resistance (Rrs) in nine normal subjects. Rrs, expressed as In the asthmatic subjects without artificially the percentage ofpreinspiration control value (ordinate), induced bronchoconstriction there was a significant was plotted in relation to time (seconds) after deep inverse correlation between the maximal change in inspiration (abscissa). The upper panel (A) shows the respiratory resistance after rapid deep inspiration results before methacholine inhalation and the lower panel and FEV,/VC (r = -0 51, p < 0.02) but not after (B) shows those after methacholine inhalation. Values are slow deep inspiration (r = -0 37, 0 05 < p < 0.1). presented as means and standard errors. *, * * Significant This shows that the more severe the initial obstruc- difference at the corresponding periods between RDI and < < tive impairment before deep inspiration the larger SDI (*p 0-05; **p 0.01). the increase of respiratory resistance with rapid on October 2, 2021 by guest. Protected copyright. bronchoconstriction in relation to bronchial sensitiv- deep inspiration. We therefore divided the asthma- ity to methacholine. At the end of the test broncho- tic subjects into two groups: one with FEVI/VC gre- constriction was reversed by inhalation of a 2% ater than 80% (FEV,/VC 84-1% (1.1%)) and the metaproterenol aerosol for 1 to 2 minutes. other with FEV,/VC less than 80% (62.2% Statistical analysis was performed with Student' s t (3.2%)). In the former group (fig 2A) there was no test or analysis of variance. The level for significant significant change in respiratory resistance after differences was taken as p < 0 05. Values are given either slow or rapid deep inspiration. In contrast, in as means with standard errors in parentheses. asthmatics with baseline FEV1/VC less than 80% (fig 2B) both slow and rapid deep inspiration Results resulted in an increase in respiratory resistance, and the increase was significantly greater after rapid than The table shows baseline spirometric data and that after slow deep inspiration (analysis of variance, respiratory resistance in the normal and asthmatic p < 0.05). In 13 asthmatic subjects in whom subjects. The FEV,/VC (%) was significantly lower bronchoconstriction was induced by a single dose of and respiratory resistance higher in the asthmatic methacholine the mean (SEM) increase in respirat- than in the normal subjects (p < 0.01). ory resistance (cm H20 l-' s-') was from 3-29 Figure 1 shows the time course of changes in (0.20) to 6-30 (0-34). In this group with artificially Thorax: first published as 10.1136/thx.39.2.86 on 1 February 1984. Downloaded from

Inspiratory flow rate and bronchomotor tone in normal and asthmatic subjects 89

Asthmatic ration at both rapid and slow flow rates was A significantly inhibited by lignocaine aerosol. The effect of rapid deep inspiration was significantly Ln greater than that of slow deep inspiration in the first 30 seconds both before and after airway anaesthesia (analysis of variance, p < 0.05). In the asthmatic subjects the transient increase in respiratory resis- tance after deep inspiration at both flow rates was also inhibited by lignocaine. B In 12 asthmatic subjects in whom dose response curves for methacholine were obtained the relation- nA rx ships between the maximal changes in respiratory resistance after deep inspiration without drug induced bronchoconstriction and bronchial sensitiv- ity to methacholine (Dmin) were compared (fig 4). The change in respiratory resistance expressed as a proportion of its control value after both slow and rapid deep inspiration showed a significant inverse C correlation with log Dmin (p < 0 05 and p < 0-01 respectively). The regression coefficients were not significantly different. Discussion

1 e *6 RDI There were four main findings in this study. Firstly, 601 o SDI in asthmatic subjects with significant airflow obstruc- Fig 2 Effects ofslow (0) and rapid (a) deep inspiration tion a rapid deep inspiration induced a greater (SDI and RDI) on changes in Rrs in asthmatic subjects. increase in bronchomotor tone than a slow inspira- A-flow effects on Rrs in 10 asthmatic subjects with normal basal bronchomotor tone (FEV /VC over 80%). The flow tion and the magnitude of the effect of rapid deep

effects showed no significant di/ference between RDI and inspiration was dependent on the degree of baseline http://thorax.bmj.com/ SD!. B-flow effects on Rrs in 12 asthmatic subjects with airway narrowing. Secondly, both the bronchocons- spontaneous airway narrowing (FEV /VC less than 80%). trictor and the bronchodilator effects of deep inspi- Rrs increased after both RDI and SDi, and the increase after ration on bronchomotor tone were partially inhi- RDI was significantly greater than that after SD!. C-flow bited by airway anaesthesia. Thirdly, broncho- effects on Rrs in 13 asthmatic subjects with constriction after both rapid and slow deep inspira- bronchoconstriction artificially increased by a single dose of tion was related to bronchial sensitivity as assessed methacholine. Rrs decreased immediately after both RDI and SDI, and the decrease was significantly greater after by the threshold value in a methacholine provoca- RDI than after SDI in the first 20 seconds. Values are tion test. Finally, in both normal and asthmatic sub- presented as means and standard errors. *Significant jects rapid deep inspiration produced greater inhibi- on October 2, 2021 by guest. Protected copyright. difference at the corresponding periods between RDI and tion of methacholine induced bronchoconstriction SDI at p < 0O05. than did slow deep inspiration. To detect the bronchomotor tone we measured induced bronchoconstriction an immediate decrease respiratory resistance using an oscillation method'2 of respiratory resistance was found after both slow rather than the more usual specific airway resis- and rapid deep inspiration (fig 2C) and, as in the tance,' -3 because it was easy to monitor simultane- normal subjects, the reduction of respiratory resis- ously both volume change and change of respiratory tance was significantly greater after rapid than after resistance during testing without any cooperation of slow deep inspiration in the first 20 seconds (paired t the patients such as a panting manoeuvre. Since test, p < 0.05). Variations in expiratory flow rate respiratory resistance reflects the total resistance of had no effect on the results. the , we had to consider the effect Figure 3 shows the effect of slow and rapid deep of tissue or chest wall resistance or both on the inspiration on bronchomotor tone before and after change of respiratory resistance. As functional lignocaine in four normal subjects with residual capacity and , however, were methacholine induced bronchoconstriction and in kept constant before and after deep inspiration, any four asthmatic subjects. In normal subjects the change of lung tissue and chest wall resistance would reduction in respiratory resistance after deep inspi- be negligible. Changes in laryngeal resistance might Thorax: first published as 10.1136/thx.39.2.86 on 1 February 1984. Downloaded from

90 Hida, Arai, Shindoh, Liu, Sasaki, Takishima A Normal Fig 3 Effect oflignocaine aerosol on bronchomotor tone after slow 1-n deep inspiration (SDI) (0) and rapid deep inspiration (RDI) (-) 0 in four normal subjects with methacholine induced -0 0 bronchoconstriction (A) and in four asthmatic subjects (B). The continuous and dashed lines show the changes in respiratory resistance (Rrs) induced by deep inspiration before and after E3 Asthmatic lignocaine aerosol inhalation 140] respectively. The effects ofdeep Ln ..- T inspiration before anaesthesia in C A SDI the four normal subjects illustrated were greater than those in the 4, 12X group as a whole (fig 1) but the -cC 1/\1~~~~ ! o'1 It j differences were not significant for --6 6 i\. Ua 6 ; ioC ~. -I I L12 either SDI or RDI. Ff - 1-1-1X- *, ** Significant difference before 60 120 and after lignocaine at p < 0.05 1 ~~S S -I--I and p <0 01 respectively.

,d Rrs also contribute to the change of respiratory resis- Rrscont 80- -*RDI tance after deep inspiration in view of the recent r =-0.71 evidence suggesting upper airway narrowing in some Olo P< 0.01 0 asthmatic patients.'' Further study would therefore 601 r=-061 be needed to show how resistance http://thorax.bmj.com/ 0 laryngeal changes 0 P<0.05 after deep inspiration in normal or asthmatic sub- 40- jects. When a subject coughed, swallowed saliva, or 0 .--.- temporarily held his breath, respiratory resistance 0 * * was transiently variable, presumably owing to glottic 0 narrowing; but otherwise the measurements were 9 *00 stable. 0- One possible explanation for the broncho-

0 ,* \ constrictor effect of deep inspiration in asthmatic -20- 9 subjects with spontaneous airway narrowing is that on October 2, 2021 by guest. Protected copyright. If the deep inspiration might mechanically stimulate 0.1 1.0 10 the irritant receptors that are located all around the Dmin unit airways.ix We have shown that a fast flow rate dur- Fig 4 Relationships between the effecits ofslow deep ing deep inspiration induced more broncho- inspiration (SDI) (0) and rapid deep iAzspiration (RDI) (-) constriction than a slow flow rate, which might be on baseline bronchomotor tone and setnsitivity to due to greater stimulation of irritant receptors at methacholine in asthmatic subjects. Thoe ordinate indicates higher flows since these will be accompanied by a the maximal change in Rrs after deep i nspiration expressed greater transmural pressure across the constricted by the percentage ofcontrol Rrs. Absciissa (logarithmic airway. If so these effects of deep inspiration should scale) indicates the cumulative dose of methacholine be inhibited by airway anaesthesia; Camporesi et a18 required to initiate an increase in Rrs (ADmin). The reported that local anaesthesia of the airway can the sensitivity to methacholine (lower L irritant and stretch increase in Rrs after either a rapid or a slonw)dhegreaterthe block both receptors receptors inspiration. and the present study showed that the flow rate Regression lines: SDI y = 21-0 - 26-2x, effects of deep inspiration were attenuated after lig- RDIy = 25-1 39..3x, nocaine inhalation (fig 3B). The results therefore ARrs suggest that the differential effect of slow and where x = log Dmin and y = rapid control Rrs deep inspiration may be at least in part a vagal Thorax: first published as 10.1136/thx.39.2.86 on 1 February 1984. Downloaded from

Inspiratory flow rate and bronchomotor tone in normal and asthmatic subjects 91 reflex. Alternative explanations for the broncho- method of obtaining dose response curves and the constrictive effect are that the greater negativity of definition of bronchial sensitivity are possible the perivascular interstitial fluid pressure during reasons for this discrepancy. We used the minimum lung inflation could cause interstitial oedema and threshold of the dose response curve as the index of narrowing of the peripheral airways,'9 or that a the bronchial sensitivity,'6 while Fish et al used the release of prostaglandin F2, might induce broncho- cumulative dose required to produce a 35% fall or constriction after deep inspiration.20 It is not known 20% fall in specific conductance or in FEV, respec- whether either of these is dependent on the inspirat- tively.2 We also examined the cumulative dose of ory flow rate. methacholine required to produce a 35% fall in Grs The bronchodilator effect of rapid and slow deep and found that this index was not correlated with inspiration in both normal and asthmatic subjects bronchial sensitivity. On the basis of our results we whose bronchomotor tone has been artificially would suggest that hyperreactivity of irritant recep- increased by methacholine may be explicable by a tors is one of the factors in increasing bronchial sen- faster flow rate during deep inspiration, stimulating sitivity to methacholine. The present study suggests stretch receptors2' and inducing more bronchodila- that the influence of deep inspiration on FEV, tation, as suggested by Beaupre and Orehek.7 Our measurements could be minimised if the forced results with lignocaine might support this explana- expiration were preceded by a slow inspiration. tion, at least in part. The fact, however, that the flow effect of deep inspiration was seen even when the We wish to express our gratitude for the preparation airways were anaesthetised suggests other mechan- of this manuscript to Ms S Omori and Mrs B isms, such as hysteresis of the airway smooth muscle Hayashi. itself. Sasaki and Hoppin22 observed that the length-tension hysteresis loop of airway smooth muscle strips with increased bronchomotor tone References tended to be larger than with relaxed smooth mus- 'Gayrard P, Orehek J, Grimaud C, Charpin J. Bron- cle. The difference between pulmonary resistance at choconstrictor effects of a deep inspiration in patients a given lung volume after deflation from TLC and with asthma. Am Rev Respir Dis 1975;111:433-9. during inflation to TLC would therefore be greater 2 Fish JE, Peterman VI, Cugell DW. Effect of deep inspi- in the constricted state. Furthermore, as a faster ration on airway conductance in subjects with allergic inspiratory flow during inspiration would be accom- rhinitis and allergic asthma. J Allergy Clin Immunol http://thorax.bmj.com/ panied by a greater transmural distending pressure 1977;60:41-6. Orehek J, Nicoli MM, Delpierre S, Beaupre A. Influence of the airway during inspiration the airway would be of the previous deep inspiration on the spirometric stretched more, which would increase airway hys- measurement of provoked bronchoconstriction in teresis. Release of bronchodilator chemical asthma. Am Rev Respir Dis 1981;123:269-72. mediators such as prostaglandin E22' during lung 4Nadel JA, Tierney DF. Effect of a previous deep inspira- inflation may also contribute to the change of bron- tion on in man. J Appl Physiol 1961;16:717-9. chomotor tone after deep inspirations. Again, how- Widdicombe JG, Nadel JA. Reflex effects of lung ever, the effects of flow on release of prostglandin E2 on inflation tracheal volume. J Appl Physiol on October 2, 2021 by guest. Protected copyright. are not known. 1963; 18:681-6. In normal and asthmatic subjects with normal 6 Nadel JA. Autonomic regulation of airway smooth mus- bronchomotor tone there was little change in cle. In: Nadel JA, ed. Physiology andpharmacology of respiratory resistance after either slow deep inspira- the airways. New York: Marcel Dekker, 1980;217- 57. tion or rapid deep inspiration. With normal bron- Beaupre A, Orehek J. Factors influencing the bron- chomotor tone inspiratory flows during deep inspira- chodilator effect of a deep inspiration in asthmatic tion would be expected to have little effect on the patients with provoked bronchoconstriction. Thorax stimulation of neural receptors or hysteretic 1982;37: 124-8. behaviour of the airways, etc. Camporesi EM, Mortola JP, Sant' Ambrogio F, Sant' We showed that the transient Ambrogio G. Topical anesthesia of tracheal receptors. increases in J Appl Physiol: Respirat Environ Exercise Physiol respiratory resistance after both slow and rapid deep 1979;47: 1123-6. inspiration were significantly correlated with bron- American Thoracic Society. Chronic bronchitis, asthma chial sensitivity (Dmin). These results seem to be at and pulmonary emphysema. Am Rev Respir Dis variance with the data of Fish et al,2 who found that 1962;85: 762-8. there was no correlation between methacholine sen- Cotes JE. Lung function, 4th ed. Oxford: Blackwell, sitivity and the amount of fall in specific 1979:371-7. conduc- Mead J. Volume-displacement body plethysmograph for tance or in FEV, after deep inspiration in asthmatic respiratory measurements in human subjects. J Appl subjects with spontaneous bronchomotor tone. The Physiol 1960; 15: 736-40. Thorax: first published as 10.1136/thx.39.2.86 on 1 February 1984. Downloaded from

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