ࡱ>  q}defghijklmnop!` Aibjbj\\ .>>aV V V V V V V $z ?4@$z 6Nu/y6y6y6y6y6y6$F8h:"6V 6V V 6...V V u/.u/..V V .(@ (Ozg,.u/606.; .;.;V ..66.6z z z D Dz z z z z z V V V V V V  Drug Targeting in Bronchial Asthma: Inhaled Corticosteroids Should Reach the Peripheral Airways P.N.R. Dekhuijzen* Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, The Netherlands Abstract: Bronchial asthma is characterised by an eosinophilic inflammatory process in the airways, and manifests itself functionally by bronchial hyperresponsiveness and variable airflow obstruction. In the past this inflammatory process was presumed to be predominantly present in the large and intermediate airways. This is not surprising since functional abnormalities in the small airways (or so-called silent zone) are much more difficult to establish in comparison to changes in the larger airways. As a consequence, changes in airway calibre and bronchial hyperresponsiveness are mainly measured in the central part of the lung, i.e. by means of the FEV1 at rest or after challenge with bronchoconstrictive stimuli like histamine and methacholine. Recently, advanced physiological, radiological and morphological studies show that the inflammatory process extends to the peripheral airways and even the alveolar compartment. This so-called peripheral inflammation is related to the clinical manifestation of the severity of asthma. Targeting the small airways with new inhaled corticosteroids with a small particle size and a high peripheral deposition may result in better control of the disease. The presence and clinical consequences of peripheral inflammation and its therapeutic approach are discussed in this re-view. INTRODUCTION Bronchial asthma is characterised by an eosinophilic inflammatory process in the airways, and manifests itself functionally by bronchial hyperresponsiveness and variable air-flow obstruction. In the long-term, airway remodelling may result in permanent damage and partly irreversible obstruction. In the past this inflammatory process was presumed to be predominantly present in the large and intermediate airways. This is not surprising since functional abnormalities in the small airways (or so-called silent zone) are much more difficult to establish in comparison to changes in the larger air-ways. As a consequence, changes in airway calibre and bronchial hyper responsiveness are mainly measured in the central part of the lung, i.e. by means of forced expiratory volume in one second (FEV1) at rest or after challenge with bronchoconstrictive stimuli like histamine and methacholine. More recent studies, however, show that the inflammatory process extends to the peripheral airways and even the alveolar compartment, and that this so-called peripheral in-flammation is related to the clinical manifestation of the se-verity of asthma. These findings and their potential therapeutic consequences are discussed in this article. In particular, the effects of the formulation of inhaled corticosteroids (ICS) with small particle sizes are presented and analysed. FUNCTIONAL CHANGES IN THE PERIPHERAL AIRWAYS Functional alterations in the peripheral compartment of the lung have always been difficult to assess because changes in the calibre of the large airways always influence measurements of the patency of small airways. Only more sophisticated measures of small airway function allow assessment of the contribution of this compartment to the in-creased airway resistance in asthma. Bronchoscopy with measurement of flow and pressure in peripheral airways (by segmental occlusion) showed that the resistance in peripheral airways is markedly increased up to 80% of total airway resistance, even in patients with mild, asymptomatic asthma (Wagner ARRD 1990) [1]. By comparison, the contribution of the small airways to the total airway resistance in normal subjects is less than 10% (Hogg NEJM 1968) [2]. In addition, uncoupling between lung parenchyma and airways occurs in the lungs of patients with asthma. This means that the normal presence of a reduction of airway resistance with increasing lung volume is absent in these patients (Irvin AJRCCM 2000) [3]. Besides, patients with asthma show a stronger tendency to collapse of the small airways (i.e. air-way closure) during expiration (King AJRCCM 1998) [4]. Quantification of this phenomenon by a single-breath nitrogen washout test revealed that this occurs more frequently in patients with severe asthma and recurrent exacerbations (int Veen AJRCCM 2000) [5]. Finally, bronchial provocation with methacholine evokes marked small airways obstruction in a subgroup of asthmatics, which is associated with pronounced bronchial hyperresponsiveness in comparison to those patients who only react with large airways obstruction (Sekizawa ARRD 1986) [6]. Together, these findings demonstrate that there are important functional changes in the so-called silent zone of asthmatics that contribute to the clinical severity of asthma. MORPHOLOGIC ALTERATIONS IN THEPERIPHERAL COMPARTMENT OF THE LUNG Several morphologic studies have revealed that the aforementioned functional changes in the peripheral compartment of the lungs are caused by infiltration of this compartment of the lung with inflammatory cells. Specifically, both biopsies taken at autopsy, surgical specimens, periph-eralbiopsies obtained by bronchoscopy and broncho-alveolar lavage (BAL) specimens have demonstrated that the typical asthmatic inflammatory process with eosinophils and T-lymphocytesis present both in bronchioli (Hamid JACI 1997) [7] (Haley AJRCCM 1998) [8] and alveoli (van Vyve Chest 1992)[9](Kraft AJRCCM 1996) [10] (Kraft AJRCCM 1999) [11]. This peripheral inflammatory process is especially pre-sent in asthmatic patients with nocturnal airflow obstruction, i.e. nocturnal asthma. In contrast, such changes are not observed in the central airway walls of these nocturnal asthmatics (Kraft AJRCCM 1996) [10] (Kraft AJRCCM 1999) [11]. Thus, asthmatics with nocturnal airflow obstruction differ from those without nocturnal obstruction by the presence of inflammatory cells in the peripheral compartment of the lung. CLINICAL RELEVANCE OF PERIPHERAL INFLAMMATION Significant correlations have been observed between the degree of nocturnal reduction of the FEV1 and the presence of inflammatory cells in the alveoli but not in the central airway wall in patients with nocturnal asthma (Kraft AJRCCM 1996) [10] (Kraft AJRCCM 1999) [11]. This part of the lung is the most important source of leukotrienes and (pro) inflammatory cytokines (Schulman JAP 1982) [12]; per mg tissue the lung parenchyma produces much more mediators involved in the cascade of the inflammatory process than the central airways. Besides, the small airways are very reactive upon stimulation with these mediators (Wolhsen AJRCCM 2001) [13]. The aforementioned correlations between peripheral in-flammation and airflow limitation in nocturnal asthma probably also occur in more severe asthmatic patients, since nocturnal asthma is a phenotype of naturally fluctuating air-flow limitation. Recently, Balzar and coworkers using trans-bronchial biopsies showed that intense inflammation occurs in the small airways of severe asthmatics (Balzar ERJ 2002) [14]. It should be noted, however, that - due to the severity of the disease - there are no studies at present directly exploring the relation between peripheral inflammation and clinical severity of the disease in severe asthmatics with recurrent exacerbations. DO INHALED CORTICOSTEROIDS (ICS) REACH THE PERIPHERAL LUNG COMPARTMENT? Administration of ICS is the cornerstone of the anti-inflammatory treatment in asthmatic patients. After passing the oropharynx the majority of particles impact in the large and intermediate airways. This is related to the mass median aerodynamic diameter (MMAD) of the inhaled preparation. In particular particles with an MMAD less than 2 micrometer reach the peripheral compartment (Fig. 1). Most dry powder inhalers(DPIs) and pressurised metered dose inhalers (pMDIs) deliver particles with an MMAD of 3-5 micrometer, or even higher if a inhalation of a DPI occurs at low flow rates (Pauwels ERJ 1997) [15].  Fig. (1). Inhaled medication and lung deposition: relationship between airway generation and particle size (MMAD). Recently an extra fine CFC-free solution of beclomethasone-dipropionate (extra fine HFA-134a-BDP, QvarTM has been developed. This pMDI fires particles with an MMAD of 0.9-1.1 micrometer (VandenBurgt JACI 2000) [16] (Leach Chest 2002) [17]. Besides, the inhalation device has been adapted, resulting in a ~70% lower spray force in comparison to the traditional CFC-containing pMDIs (Gabrio IJP 1999) [18]. Together, these changes result in a high lung deposition of 50-60% of the label claim, in comparison to less than 15% with CFC-BDP and the CFC-containing pMDI with fluticasone propionate (FP) (Leach Chest 2002) [19] (Leach ERJ 1998) [17]. This is very well in line with the differences in MMAD between the preparations mentioned, i.e. extra fine HFA-134a-BDP, 0.9-1.1 micrometer; CFC-BDP, 3.5 micrometer; and CFC-FP, 2.0 micrometer (Leach Chest 2002) [17].  Fig. (2). MMAD of several inhaled corticosteroids.  Fig. (3). Deposition of radio labeled after inhalation of extra fine HFA-134a-beclomethasone, cfc-fluticasone and cfc-beclomethasone. Not only the amount of drug reaching the lower airways, but also the pattern of distribution of pulmonary deposition is important. Extra fine HFA-134a-BDP has a relatively higher peripheral deposition compared with CFC-BDP and CFC-FP (Leach Chest 2002) [17]. This is of importance in terms of potential efficacy in the peripheral compartment of the lung, since the concentration of steroid receptors is highest in this part of the lung (Adcock AJRCCM 1996) [20]. Thus, an ICS with a low MMAD and thus high peripheral lung deposition may be expected to have more effects than an ICS with a higher MMAD and lower peripheral lung deposition. ARE ICS ABLE TO MODULATE THE INFLAMMATORY PROCESS IN THE PERIPHERAL COMPARTMENT? Mechanistic studies have been directed towards the question if ICS can modulate the inflammatory process in the peripheral compartment of the lung. CFC-FP was shown to reduce bronchial but not alveolar nitric oxide (NO) output in asthmatics, suggesting that the usual ICS do not influence inducible nitric oxide synthase (iNOS) expression in peripheral airways in these patients (Lehtimaki ERJ 2001) [21]. In another study, extra fine HFA-134a-BDP, but not CFC-BDP, was demonstrated to modulate the immunologic reactivity of alveolar macrophages (Marshall ERJ 2000) [22]. A study using high-resolution computed tomography (HR-CT) has shown that extra fine HFA-134a-BDP can attenuate regional hyperinflation induced by inhalation of methacholine in asthmatic patients, in contrast to CFC-BDP (Goldin JACI 1999) [23]. In addition, when HFA-134a-BDP and CFC-fluticasone were compared directly at a 1: 1 microgram ratio, HFA-134a-BDP showed superior effects on baseline closing volume (CV), CV/VC ratio, and postbronchodilator FEF25-75% (Thongngarm J Asthma 2005; 42: 257-263) [24]. Together, these data indicate that the inflammatory process in the peripheral compartment of the lung can be modified by ICS with a low MMAD and high peripheral deposition in contrast to those with a high MMAD and low peripheral deposition, and that these changes are accompanied by functional improvements.  Fig. (4). Change from baseline in symptom free days (upper panel) and nights (lower panel) [39]. DO ICS WITH HIGH PERIPHERAL DEPOSITION IMPROVE CLINICAL OUTCOME? One of the consequences of the application of ICS with a low MMAD and high lung deposition is that the dose delivered to the patient can be lowered compared with the dose of an ICS with a high MMAD and low lung deposition. Indeed, in a large clinical trial Busse et al. showed that the dose-response curve for a change in FEV1 and in measures of small airways patency (forced expiratory flow rate in the mid-expiratory flow rate, FEF-25-75%) was shifted to the left with extra fine HFA-134a-BDP compared with CFC-BDP (Busse JACI 1999) [25]. It was calculated that it would take 2.6 times the dose of CFC-BDP to produce the same amount of improvement in FEV1 obtained with extra fine HFA-134a-BDP, and 3.2 times the dose of CFC-BDP to produce the same amount of improvement in FEF25-75%. Several comparative studies have confirmed this 2: 1 dosage ratio in both adults (Davies RM 1998) [26] (Gross Chest 1999) [27] (Worth Respir 2001) [28] (Reichel IJCP 2001) [29] (Fireman AAAI 2001) [30] (Price Pharmaceconomics 2002) [31] (Boulet CRJ 2004) [32] and children with asthma (Pedersen Ped 2002) [33] (Szefler JACI 2002) [34]. Besides, when extra fine HFA-134a-BDP was compared with CFC-FP, an ICS with an about 1.5-2 times higher potency than BDP, a 1: 1 ratio was demonstrated (Aubier RM 2001) [35] (Molimard Respir Med 2005) [36] (Lasserson Cochrane Database Syst Rev 2005) [37]. Of par-ticular importance was the finding in several of these studies that extra fine HFA-134a-BDP resulted in significant improvements in quality of life, symptom scores and asthma control compared with the double dose of CFC-BDP or budesonide and a similar dose of CFC-FP, despite similar outcomes in lung function (Worth Respir 2001) [28] (Juniper Chest 2002) [38] (Ederle, Eur Rev Med Pharmacol Sci 2003) [39] (Van Schayck IJCP 2004) [40]. A significant improvement in asthma control has even been shown in patients receiving long-acting beta-agonists besides their traditional ICS, suggesting potential advantages for HFA-134a-BDP extra fine aerosol as part of anti-inflammatory treatment optimization (Molimard Respir Med 2005; 99: 770-778) [36]. Besides the benefits of increased peripheral deposition, another beneficial effect of extra fine HFA134a-BDP is its reduced oropharyngeal deposition (from 60-70% to less than 30%), resulting in less oropharyngeal side-effects (Thomp-son Respir Med 1998) [41]. Itmight be expected that increased lung deposition would be associated with increased systemic effects like suppression of cortisol production. Clinical comparative studies, however, have shown that this is not the case (Harrison JPP 1999) [42] (Boulet CRJ 2004) [32]. It has been postulated that this lack of cortisol suppression is associated with the pharmacokinetics of extra fine HFA-134a-BDP; due to its small particle size maximum serum concentrations after in-halation are higher but sooner reached compared with CFC-BDP(Tmax 30 min vs. 2-2.5 h, respectively). This low Tmax may affect the hypothalamic-pituitary-adrenal (HPA)-axis less, resulting in less adrenal suppression (Dekhuijzen RM 2000) [43] (Harrison J Aer Med 2002) [44]. CONCLUSIONS There is increasing evidence that peripheral inflammation is present in patients with asthma, contributing to the clinical presentation of the severity of the disease. Mechanistic studies show that ICS with a low MMAD and a high peripheral lung deposition can modulate the immunologic and functional characteristics of the peripheral lung compartment, in contrast to ICS with a high MMAD and low peripheral lung deposition. This is reflected in a 2-2.5 lower dose of ICS required to achieve superior asthma control compared with the traditional ICS in both adults and children. The extend to which ICS with a low MMAD can achieve superior clinical efficacy besides the already demonstrated improvements in QOL in patients with severe asthma despite high doses of traditional ICS and oral corticosteroids is the subject of cur-rent studies. REFERENCES [1] Wagner EM, Liu MC, Weinmann GG, Permutt S, Bleecker ER. Peripheral lung resistance in normal and asthmatic subjects. Am Rev Respir Dis 1990; 141(3): 584-8. [2] Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 1968; 278(25): 1355-60. [3] Irvin CG, Pak J, Martin RJ. Airway-parenchyma uncoupling in nocturnal asthma. Am J Respir Crit Care Med 2000; 161(1): 50-6. [4] King GG, Eberl S, Salome CM, Young IH, Woolcock AJ. Differ-ences in airway closure between normal and asthmatic subjects measured with single-photon emission computed tomography and technegas. Am J Respir Crit Care Med 1998; 158(6): 1900-6. [5] Veen JCCMi',Beekman AJ, Bel EH, Sterk PJ. Recurrent exacerba-tions in severe asthma are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med 2000; 161(6): 1902-6. [6] Sekizawa K, Sasaki H, Shimizu Y, Takishima T. Dose-response effects of methacholine in normal and in asthmatic subjects. Rela-tionship between the site of airway response and overall airway hyperresponsiveness. Am Rev Respir Dis 1986; 133(4): 593-9. [7] Hamid Q, Song YL, Kotsimbos TC, Minshall E, Bai TR, Hegele RG, Hogg JC. Inflammation of small airways in asthma. J Allergy Clin Immunol 1997; 100(1): 44-51. [8] Haley KJ, Sunday ME, Wiggs BR, et al. Inflammatory cell distri-bution within and along asthmatic airways. Am J Respir Crit Care Med 1998; 158(2): 565-72. [9] Van Vyve T, Chanez P, Lacoste JY, Bousquet J, Michel FB, Go-dard P. Comparison between bronchial and alveolar samples of bronchoalveolar lavage fluid in asthma. Chest 1992; 102(2): 356-61. [10] Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. Alveo-lar tissue inflammation in asthma. Am J Respir Crit Care Med 1996; 154(5): 1505-10. [11] Kraft M, Martin RJ, Wilson S, Djukanovic R, Holgate ST. Lym-phocyte and eosinophil influx into alveolar tissue in nocturnal asthma. Am J Respir Crit Care Med 1999; 159(1): 228-34. [12] Schulman ES, Adkinson NF Jr, Newball HH. Cyclooxygenase metabolites in human lung anaphylaxis: airway vs. parenchyma. J Appl Physiol 1982; 53(3): 589-95. [13] Wohlsen A, Uhlig S, Martin C. Immediate allergic response in small airways. Am J Respir Crit Care Med 2001; 163(6): 1462-9. [14] Balzar S, Wenzel SE, Chu HW. Transbronchial biopsy as a tool to evaluate small airways in asthma. Eur Respir J 2002; 20: 254-259. [15] Pauwels R, Newman S, Borgstrom L. Airway deposition and air-way effects of antiasthma drugs delivered from metered-dose in-halers. Eur Respir J 1997; 10(9): 2127-38. [16] Vanden Burgt JA, Busse WW, Martin RJ, Szefler SJ, Donnell D. Efficacy and safety overview of a new inhaled corticosteroid, QVAR (hydrofluoroalkane-beclomet has one extrafine inhalation aerosol), in asthma. J Allergy Clin Immunol 2000; 106(6): 1209-26. [17] Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. Lung depo-sition of HFA-beclomethasone is greater than that of CFC-fluticasone and CFC-beclomethasone: A cross-over study in healthy volunteers. Chest 2002; 122: 510-6. [18] Gabrio BJ, Stein SW, Velasquez DJ. A new method to evaluate plume characteristics of hydrofluoroalkane and chlorofluorocarbon metered dose inhalers. Int J Pharm 1999; 10: 186(1): 3-12. [19] Leach CL, Davidson P, Boudreau R. Improved airway targeting with the CFC-free HFA-beclomethasone metered dose inhaler compared with CFC-beclomethasone. Eur Respir J 1998; 12: 1346-53. [20] Adcock IM, Gilbey T, Gelder CM, Chung KF, Barnes PJ. Gluco-corticoid receptor localization in normal and asthmatic lung. Am J Respir Crit Care Med 1996; 154(3 Pt 1): 771-82. [21] Lehtimaki L, Kankaanranta H, Saarelainen S, Turjanmaa V, Moilanen E. Inhaled fluticasone decreases bronchial but not alveo-lar nitric oxide output in asthma. Eur Respir J 2001; 18(4): 635-9. [22] Marshall BG, Wangoo A, Harrison LI, Young DB, Shaw RJ. Tumour necrosis factor-alpha production in human alveolar macro-phages: modulation by inhaled corticosteroid. Eur Respir J 2000; 15(4): 764-70. [23] Goldin JG, Tashkin DP, Kleerup EC, et al. Comparative effects of hydrofluoroalkane and chlorofluorocarbon beclomethasone dipro-pionate inhalation on small airways: assessment with functional helical thin-section computed tomography. J Allergy Clin Immunol 1999; 104(6): S258-S267. [24] Thongngarm T, Silkoff PE, Kossack WS, Nelson HS. Hydro-fluoroalkane-134A beclomethasone or chlorofluorocarbon flutica-sone: effect on small airways in poorly controlled asthma. J Asthma 2005; 42(4): 257-63. [25] Busse WW, Brazinsky S, Jacobson K, et al. Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant. J Al-lergy Clin Immunol 1999; 104(6): 1215-22. [26] Davies RJ, Stampone P, Oconnor BJ. Hydrofluoroalkane-134a beclomethasone dipropionate extrafine aerosol provides equivalent asthma control to chlorofluorocarbon beclomethasone dipropionate at approximately half the total daily dose. Respir Med 1998; 92 (suppl A): 23-31. [27] Gross G, Thompson PJ, Chervinsky P, Vanden Burgt J. Hydro-fluoroalkane-134a beclomethasone dipropionate, 400 microg, is as effective as chlorofluorocarbon beclomethasone dipropionate, 800 microg, for the treatment of moderate asthma [see comments]. Chest 1999; 115(2): 343-51. [28] Worth H. Comparison of hydrofluoroalkane-beclomethasone dipropionate autohaler with budesonide Turbuhaler in asthma con-trol. Respiration 2001; 68: 517-26. [29] Reichel W, Dahl R, Ringdal N, Zetterstrom O, van den Elshout FJ, Laitinen LA. Extrafine beclomethasone dipropionate breath-actuated inhaler (400 micrograms/day) versus budesonide dry powder inhaler (800 micrograms/day) in asthma. Int J Clin Pract 2001; 55(2): 100-6. [30] Fireman P, Prenner BM, Vincken W, Demedts M, Mol SJ, Cohen RM. Long-term safety and efficacy of a chlorofluorocarbon-free beclomethasone dipropionate extrafine aerosol. Ann Allergy Asthma Immunol 2001; 86(5): 557-65. [31] Price D, Haughney J, Duerden M, Nicholls C, Moseley C. The cost effectiveness of chlorofluorocarbon-free beclomethasone dipropi-onate in the treatment of chronic asthma: a cost model based on a 1-year pragmatic, randomised clinical study. Pharmacoeconomics 2002; 20(10): 653-64. [32] Boulet LP, Cartier A, Ernst P, Larivee P, Laviolette M. Safety and efficacy of HFA-134a beclomethasone dipropionate extra-fine aerosol over six months. Can Respir J 2004; 11(2): 123-30. [33] Pedersen S, Warner J, Wahn U, et al. Growth, systemic safety, and efficacy during 1 year of asthma treatment with different beclo-methasone dipropionate formulations: an open-label, randomized comparison of extrafine and conventional aerosols in children. Pe-diatrics 2002; 109(6): e92. [34] Szefler SJ, Warner J, Staab D, et al. Switching from conventional to extrafine aerosol beclomethasone dipropionate therapy in chil-dren: a 6-month, open- label, randomized trial. J Allergy Clin Im-munol 2002; 110(1): 45-50. [35] Aubier M, Wettenger R, Gans SJ. Efficacy of HFA-beclomethasone dipropionate extra-fine aerosol (800 microg day(-1)) versus HFA-fluticasone propionate (1000 microg day(-1)) in patients with asthma. Respir Med 2001; 95(3): 212-20. [36] Molimard M, Martinat Y, Rogeaux Y, Moyse D, Pello JY, Giraud V. Improvement of asthma control with beclomethasone extrafine aerosol compared to fluticasone and budesonide. Respir Med 2005; 99(6): 770-8. [37] Lasserson T, Cates C, Jones AB, Steele E, White J, Lasserson T. Fluticasone versus HFA-beclomethasone dipropionate for chronic asthma in adults and children. Cochrane Database Syst Rev 2005; (4): CD005309. [38] Juniper EF, Price DB, Stampone PA, Creemers JP, Mol SJ, Fire-man P. Clinically important improvements in asthma-specific qual-ity of life, but no difference in conventional clinical indexes in pa-tients changed from conventional beclomethasone dipropionate to approximately half the dose of extrafine beclomethasone dipropi-onate(*). Chest 2002; 121(6): 1824-32. [39] Ederle K. Improved control of asthma symptoms with a reduced dose of HFA-BDP extrafine aerosol: an open-label, randomised study. Eur Rev Med Pharmacol Sci 2003; 7(2): 45-55. [40] van Schayck CP, Donnell D. The efficacy and safety of QVAR (hydrofluoroalkane-beclometasone diproprionate extrafine aerosol) in asthma (part 1): an update of clinical experience in adults. Int J Clin Pract 2004; 58(7): 678-88. [41] Thompson PJ, Davies RJ, Young WF, Grossman AB, Donnell D. Safety of hydrofluoroalkane-134a beclomethasone dipropionate extrafine aerosol. Respir Med 1998; 92 (suppl A): 33-9. [42] Harrison LI, Colice GL, Donnell D, Soria I, Dockhorn R. Adrenal effects and pharmacokinetics of CFC-free beclomethasone dipro-prionate: a 14 day dose-response study. J Pharm Pharmacol 1999; 51(3): 263-9. [43] Dekhuijzen PNR, Honour JW. Inhaled corticosteroids and the hypothalamic-pituitary-adrenal (HPA) axis: do we understand their interaction? Respir Med 2000; 94(7): 627-31. [44] Harrison LI, Kurup S, Wagner C, Ekholm BP, Larson JS, Kaiser HB. Pharmacokinetics of beclomethasone 17-monopropionate from a beclomethasone dipropionate extrafine aerosol in adults with asthma. Eur J Clin Pharmacol 2002; 58(3): 197-201. `ast`    1Pm<3tu|Qj#AB!"1Pe &!'!!!! "$$A%B%h;Clhfh0h\$0J5CJhsh\$0J5CJaJ hsh8 Fhs hshsPat  uB$B%e&'''(|+gdf$a$gd0gdfgdfgd;Clgdsgdsgd0gd0 $7$8$H$a$gd\$gdsgdsgdf#gdsiB%d&e&'''''''((/(0(5(T(l(m(L)k)++{+|+}+~++++++++++,,!,",%,&,9,:,S,s,,,--....//'/F/L0k00011)3H3*4+4F4e4{4|4}4~4jKh0UhOZ_ h0h0jh0Ujh0Uh;Cljh0Uh0hf hfhfhs hshsH|+}++++:,./|4}444#5hAvADDDoEFF~GKHJIIgdOZ_gdfgdOZ_gd0gd0gd0gdf$a$gd0gdf~4444"5#55567778 9%9D999:::;E<Y<s<< = ===>>??gAhAuAvAB.B|BBDDDDDD EnEoErEsEFF F FFFFF}G~GGGGJHKHNHOHIIJIMIOIĹhzhzmHsHhzhOZ_mHsHhz hOZ_hOZ_hOZ_mHsHhfhfmHsHhOZ_hf hfhfh0IOIIIIIJJJJOKPKTKVKKKKKLLLLLLDMEMIMKMMMMMQNRNVNXNNNOOOOOOPPPPPPPPPQQQQQCRcRdRhRjRRSSSSSȽתתhOZ_hOZ_mHsHhzmH sH hzhzmH sH hzhOZ_mH sH h0hzmHsHhzhzmHsHhzhOZ_mHsHhz hOZ_hOZ_CIJPKKLEMMRNNPPQdRSSTUVWXYhZz[Z\x]9^^_E`1abgdOZ_SSSSSTTTTTTUUUUVVVVWWWWWWXXXXYYYYgZhZlZnZy[z[~[[Y\Z\^\`\w]x]|]~]^8^9^=^?^d^]_^_b_d_`D`E`I`K`ļhzmHsHhOZ_hOZ_mHsHhzmHsHhzmHsHhzhzmHsHhzhOZ_mHsHhfhOZ_mHsHhOZ_hOZ_mHsHhOZ_ hOZ_hOZ_hz?K`0a1a5a7abbb bbbbbbIdJdNdPdddeeeeeeffffogpgtgvgh h$h&hiih'O hfhfhz hOZ_hOZ_hzmHsHhOZ_hOZ_mHsH(bbJddefpg hiigdfgdOZ_ 8 00P:p0/ =!"#8$% N 00P:p0/ =!"#$% P0 hDd" nnP  C ,Afig-1-newR?h 3hXDFh 3hXJFIF ExifMM*bj(1r2iAdobe Photoshop 7.02004:10:18 00:46:41(& HHJFIFHH Adobe_CMAdobed            ]"?   3!1AQa"q2B#$Rb34rC%Scs5&DTdE£t6UeuF'Vfv7GWgw5!1AQaq"2B#R3$brCScs4%&5DTdEU6teuFVfv'7GWgw ?I+ZI$7Yv вpꪡeWz۝ [m浬=FPÙ2LF$Ey!wZZ-D?OR?qS1%-?ORU,_OMBY-cH:O >* _i&?OQ82wx鴷qLc{_plG* MfyobfeDnݤ{_CucШI+ZI$I%)$IHsΠvDc׷G#;.Uucr<G"t1= A)ѨI+ZUkl- Ao@Ab(T 2)}{4gwV5̮ .~¯)Jo7wKOeM2g{"7a[*LnsP}lX=ُ'tmU-_ʝ<>-J|ҕ` iT- O!r xZrk hKcJl\w§14Fւ= N4 omW7\ߚؠ A6Ҩ)zhk}RR-▊װVpKKZCO&. ;< ~Dt*?z^xz◨)_+/\욅V})-xEx0'p;|Od}#eۢ?_meq p|?v1#_/Q~GKnZ?*Uscɒ[b7UQS8x LouWhYpenux+OuX"qJݻ7iߐ<Ө7+_))C{J߂TT͹5.y!q3%9nԟ{nח9A#FEB߂E\\H`FtkgNM1Q)t|=r3?41$3%R)o{qM<2x͇mPue5 ?1Wz)ǘ4@tDpqz{'"d%19Or<_{Cw8u@tJ[&aQOwusv?E!&3 B'?b6srs$6;a>~/)K|7;GOK|-?b߂PV?1Rvmи;2$}-M 8n:;~GէԨ3P?jc))C?x of ὧkoglڕ?s e5&?"?i>^7w? GO7]gq`&,g ll2V.Z{qzw+@`,-jca_llomm{}NhupxE]KlQsMWܖx8D)C4/hzP?j2HAJP?iC?x1IJ(g4c*mp8G43#?%vߥKmmPhotoshop 3.08BIM%8BIM8BIM&? ??8BIM 8BIM8BIM 8BIM 8BIM' 8BIMH/fflff/ff2Z5-8BIMp8BIM$@@P:78BIM8BIMG fig-1-newnullboundsObjcRct1Top longLeftlongBtomlongRghtlongslicesVlLsObjcslicesliceIDlonggroupIDlongoriginenum ESliceOrigin autoGeneratedTypeenum ESliceTypeImg boundsObjcRct1Top longLeftlongBtomlongRghtlongurlTEXTnullTEXTMsgeTEXTaltTagTEXTcellTextIsHTMLboolcellTextTEXT horzAlignenumESliceHorzAligndefault vertAlignenumESliceVertAligndefault bgColorTypeenumESliceBGColorTypeNone topOutsetlong leftOutsetlong bottomOutsetlong rightOutsetlong8BIM8BIM<8BIM ] JFIFHH Adobe_CMAdobed            ]"?   3!1AQa"q2B#$Rb34rC%Scs5&DTdE£t6UeuF'Vfv7GWgw5!1AQaq"2B#R3$brCScs4%&5DTdEU6teuFVfv'7GWgw ?I+ZI$7Yv вpꪡeWz۝ [m浬=FPÙ2LF$Ey!wZZ-D?OR?qS1%-?ORU,_OMBY-cH:O >* _i&?OQ82wx鴷qLc{_plG* MfyobfeDnݤ{_CucШI+ZI$I%)$IHsΠvDc׷G#;.Uucr<G"t1= A)ѨI+ZUkl- Ao@Ab(T 2)}{4gwV5̮ .~¯)Jo7wKOeM2g{"7a[*LnsP}lX=ُ'tmU-_ʝ<>-J|ҕ` iT- O!r xZrk hKcJl\w§14Fւ= N4 omW7\ߚؠ A6Ҩ)zhk}RR-▊װVpKKZCO&. ;< ~Dt*?z^xz◨)_+/\욅V})-xEx0'p;|Od}#eۢ?_meq p|?v1#_/Q~GKnZ?*Uscɒ[b7UQS8x LouWhYpenux+OuX"qJݻ7iߐ<Ө7+_))C{J߂TT͹5.y!q3%9nԟ{nח9A#FEB߂E\\H`FtkgNM1Q)t|=r3?41$3%R)o{qM<2x͇mPue5 ?1Wz)ǘ4@tDpqz{'"d%19Or<_{Cw8u@tJ[&aQOwusv?E!&3 B'?b6srs$6;a>~/)K|7;GOK|-?b߂PV?1Rvmи;2$}-M 8n:;~GէԨ3P?jc))C?x of ὧkoglڕ?s e5&?"?i>^7w? GO7]gq`&,g ll2V.Z{qzw+@`,-jca_llomm{}NhupxE]KlQsMWܖx8D)C4/hzP?j2HAJP?iC?x1IJ(g4c*mp8G43#?%vߥKmm8BIM!UAdobe PhotoshopAdobe Photoshop 7.08BIM<>k>k>k kk.k"QkvQkvQkv8OkLDBk=ZLk.qjjjjjji"i1i@L2iqd il{igijij^iji{<imsiWj$j$j$ڳjiڳjiڳji>k>k>k͠k{}͠k{}͠k{};+kZ;+kZ;+kZlXlXlX#llplqlvlalx'lo olSolSolS8BIMHhttp://ns.adobe.com/xap/1.0/ adobe:docid:photoshop:e8294dc2-20d7-11d9-b42a-9696b6a1baea Adobed@P     u!"1A2# QBa$3Rqb%C&4r 5'S6DTsEF7Gc(UVWdte)8fu*9:HIJXYZghijvwxyzm!1"AQ2aqB#Rb3 $Cr4%ScD&5T6Ed' sFtUeuV7)(GWf8vgwHXhx9IYiy*:JZjz ?}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺uı"ߺzRA7Qૹ2_7~eϋ?0biӟ_D{ߺ^׽u3\W1xhEym?s_r_wׯ{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{ÇZOt9ҟr-u}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺ur?:ߺzo3q=ߘ'D%{m:q 蛯{^׺umw[xr<W^r_*4׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^nǷ?֓$_܋}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺ur?:ߺzo1ן7Ioo]ktQWN>]~{ߺ^ӎڈʞ?o_r/yQџ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺOs>=v'r?==m[E}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u̱Du^ _mɖ yߙz',^m:r 蛯{^׺u6`CpAfp)Ѓ畿u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽t?۟pkIg/SE_}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺uCz/h0xKcso={3R?n{{^׺wB֣kmmZdPGЃGQte׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^nÃݭ'IOO[Q:}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u!+!}=u][5 Q?Oʉ?_ϼ*W9[_eN]s~t1W^׽u~=lyF..滳,dЇ-y,]y?я^׽u~{ߺ^׽u~{ߺGOcl7Gi뭈 nGăd*kbhC/[a7xqOqQ{ŬwxX-ma"`h{d%C||~l+ɿo;Fi!#I,< e,Bzר7w|tc'nDvo]o,~?ud^-_Ld41!Iuou䏻ގs˕{孨;5J}oKo #;1pF[iX.8鵹]T$Uݝ[ٛs&), 9L_kٻI T8h!Ts;S+qs;=W)a% sO+F&>#VFZI4h::v^yŭm:GwXXw^ 9 kxwf3]s@n יd+j-){-5MDE >R)?_$ٟ=ItqoV|zCpmZٶ ]HL2(B&1^{_;r]=};<7@ Ȳ+ҁIj ۪>ZmWLش].Gs,\y:|>^<;ּii=śއFYǾ\߹o{ܖW HAU) ZbOB/i=ilRXX-ycVMUrIWmOĬDb7dA˒ߙ7E UXk.4Q=TrкJu{{6/wُ=rwRmaV`,u]jvFVFWi-J ͢㞽ةybp9KOqqPUŔ:j>=uNsqv?w7Llݧ>~n_26ےe?p:=bdL১u9//||9zb,~ESw|xf1 24r>ú#yܽaoxF?NHOs1Nu6fdn}Ի3!oYd"h 3ċ+#i~|=]v˘OцN϶De9T}L(4TuGm4n]k:]8+'JJ=a靏kj>7wOC7GTƣwH54b[QG,(tϥzu_sMs1`Vvon.^)ȝ%HGY<-Q.zl{|~%ݶA ^ڋ3)(ͥXFQ}ڽ7]otW[)vz钪oTx/Fuɻ9{GQ sFsOmWI k2 -c{{ܗ<g/H`H-b`9Ӡޕzݹ{_Dkq&RZ]&v)S5&]wpggHom<6HmD-%_LIE.mڟnxgecl%Fky!k22Z^Ý,up5Un^wG5o &tU_]o"H9 gP}y}]6y7ll0Exʎag$q}͏ˆkq}cw]q#x3uc+0̵n}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺uO ce c"f'8^no`&Ms4/2s{9sx:mğײ>u{{^cnH?]@a0{,br.}?w#gh#5ty9cmgxo퐢^ܪ28,^3FHk_n9ۮWOs.s؞Ag}k +u4D{-+ QJDL?N}lc7V3諲To͗x\&Gp馎M}BiXeH(,_}f~[7n5ܫYaVlۮ ($RMXH R0n~zf>VQPw"I;FQkP؅A:~uWKMË<6=r}Yl֮IgɬJYR{˙e} ]h-$—~ )=ЀnB'Hj=nAgIT-mvj q4H`Gj}\׺u{{^׺u{{^׺u{{^׺u{{^׺u[ G۹0fWy5+0JUSx'm-cl}o[}}Fw=eXԞ-ǭj5.Xۭ~eݦW]_MD6,hhhz>5$uCl}SM<^,UlQR54ԮTq~p>}y9݋m+ܑ{Z[5#],EDe4rqP}/l9siMJ%Z#$T&ֵԽ*{oXl?ΩS# KUɈ>D #E2ܴE|MKK-=mAjU%L Ivx؈@s޷;mV<vbP3(VrY߉}?J;Pˇ/d )zHj[Ȧwοk|~ߝfQjuWÁ+ 9&:2#ktػ~yI5-Ti5A`zggí귿enX&o iAÉJ .6'3$5mU7I5 *@~}}~=Գ{=H,8o7kS[+,b5:r8trBndIaD!ZFGuZLGV`D[mC3$pl6禮{U@j!|KoekGŔLcZU]9Icu<@zl]3;PuJ:/bcḟH}>?x~E{C_r\ѵ,"kEC#w/l>u 97%.7HqFPmrz}*4n]r7bjeo#_TJ35=DV`h9fj4${}_w~{}ǯ{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{ÇZOt9ҟr-u}\׺u{{^׺u{{^׺u{{^׺u{{^׺uM3W!1_z?h3+O^93W8O?qG1/  Z\,Y |eLۏ>w9#ߵtϼ.۳I=5w!{uu7w Xqt~y=#g"'4aP|q>=׽"޽GZILf7ccmݳI[V\ĕ7!Mv7ݷtݧ,(ۄD[Φ`nbNc?+^YN[GlN]S 2?a2PIfn> TYfcc.{ڔ`ڷ~(Xu# 3ۑvmaxGnOm5_+#enuqđ]V)P(L\MhEo[>}>KיgiVɎ;tgU<)D5,,fۥ ^y)`={ٸlF_{#M$J|>?3KUO+F(1R~7#mx=o߷?w7#{3s-ͥ/s5koj8\@z|XsGs6V5ŴSBĒ+df4H&'# v>z{+&]Rd6櫚%% Y]ҔΥ'[*eCx l(RIܭܷ텷w2n>U +!}>,IӭutY:YN>cC62i+lSHA,L'[}]xܷz ɴ;F) WVR du ]gx>},otK8u[pˤI@G˓in]{/F/>L&K1Vh#78Yզ"I,ѼHX)pGRj9LUm:xr5ՐEkx88ߋ{i5׵\ɮ XbvQ6R>dt$= u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~ݳPizfSZh A *O:[S $\:(q"84#@$^%oRO럺{{^׺S ʹ>}g _dyvoK/ʝvv)WW?y/я^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺOs>=v'r?==m[E}\׺u{{^׺u{{^׺u{{^׺u{{^׺uz籒$Y<N1HxUE[G$xDIVေUl2[.n3;ӪFhgC ( ͺj,7K' ym2K 6Ppxt?P| gi;q߻KnW4FXZ"$]}^.nx[ֱ}m;|Q#}Po  B1:}*˝?pxW/-VW#1IH =6Nra)gg{}AjZk =Me{]s׶˴5rUm,.e(-4jQRx]Nf-RO}{ɩ{PU[9JuȧYHA%eJAʪ*]f\vG03n^[gKb6*hGޏl9mZܫ%hDIf|"}zS?tw>tq6A8 q%,XcO(df/mZa4 ?w)Q"{ )JӤtp|u~{܇bZe"Z$ZVVtnݡO;tett"t4([?wv|Y=ǰ#i!+oDݏ!<@5G'S$y~K],\]̱jL(:(tJ*&:^-ߏ[ uF[MOS)J\3UTpKKA._L?nDznGexY q$RG*QuaMJjUk/'}/ -97UXŽdRJkC t1׵{Ƴio]~mLTnb )tN1GdKZ{6ˑl9g6x,fxfB *րu!r?R~`حfK滸CV ʧ *UqZ>wy| [z]RWﰸJzQQD(qT,$f>þs\zת}zT?{^S׬?mzׯXAߺO^u^ao~>zת}zT?{^S׬?mzׯXAߺO^u^ao~>zת}zT?{^S׬?mzעR5Wnɳ(WJ5{}ҽ\hp Ux[^!9h1U/@{{^׺u4?ܾr zp?}}<ϸX?z˸?XڰʧׯXAߺO^u^ao~>zת}zT?{^S׬?mzׯXAߺO^u^ao~>zת}zT?{^S׬?mzׯXAߺO^u^ao~>zת}zxۀx>'r?==lO[:}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺ukfw+Mt[/ MP7xs?[2{=ma5NR0%l,m?eo>!"]u{{^׺\T=hx7Ձܣ.s k2`z?>?OΖz=>{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u6|{si=OJzzȷ}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u|mܵV3r3(+Vm#O_,KYOUN#SIOvB<.v tH fj@@twF*t4 C6%;'v&?him)[ă&k窂@gǰ+o;]ʖ;2iO{#v Mزi>A|%CUjuLUtYfPR:ǹGyb1Y?ߺo{^׺us٪-ni+rᡧy)eD`=X<':vy>'`?o8f8MO%~Tffjd7iZa D=?7gyuCV?IڟF[^n DWE{ߺ^׽u~DC>9nL[0==~xVO/mo`4K08P\}u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^nÃݭ'IOO[Q:}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺(v&{)Kmv(Y;o<)j롧hc3+T/RY\cr4[ڭńp:st6@(%N"sZj$4KRj0QHO3sqI&Z u5.9gL^LM3*Y%TTO%yXzUQaz狎r kdśw#aG$wMokh,$f8.hP0̒OX>:zroO+QSٓJ\VJzLno#NE-e%-U==SZ3FNٳo{i5mZXaZe-IF>~OxЏצ:u{{^׺u{{^׺u{{^׺u{{^׺u{{^nǷ?֓$_܋}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^l7"ut4&,TSUI; JUDM70\^\5-⍝,EK4B*}Af? }|ec<;SB5COSRWU#ZJF?cm}t7[%g?-GQE!>.oQrCSt{^fZUe궦mhݴ#=^5AIf4i52+ 5Sl9& H7V,H8j6y&;iQ0Vz"SSSO U%\RSȳSTFQJK 8e`lT$z\̎84 q7u^{utJ}DT4!穨cRȍ#hI8Syh&ܵ1MAI=ĸݹECjQDMD+52{os9s2Ljl281q@W}dK8\5(Md[UqD}{ߺ^׽u~{ߺ^Ԝ6lI1PW}@lf$db$&f>lᅱ%N S7e2uہi+UXNJ *7bx61!RC]mpRT ?QO ث+77GU+"GSu~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺOs>=v'r?==m[E}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^i곛CfSCUML(6,5s=${naaD҈kGz-TUu>hw>UTzz}@{{^׺Ya\0$g+ZJ]W;tPN:B]GGo˛P @0#s =/m;(0)@'AJHh#IXfUhD`U`n*J!럿uOz9BOb60OM:xkMmk-7{8p_ҿ5 \kiu%RPx<ҧO@%p@{{^׺u{{^׺u}WcWmf͐:G"2N`Z~s$}G/9?F2|1c_0o(x6OߐA H AQk{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^nÃݭ'IOO[Q:}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^&tQi)Iq9>7t^AZ<8x&QDaǴ6{;Mg # b< vHUqFFV09tR7V={W61aIk$s 0,5)AcIR1 kkA6鰇Y>)ad_fGI.h]Sw/wt}_'X/.Z*P*(>gI$+Hzu{{^fSh!CBµuPә@eB%tp \>ZmO-<*4g ^Oϥ0Yܬmk$U-OөA9pAG^&z{ߺ^x*礪'H* ^9aJI}Z ʹe`hU ӑ$2G4.VT`T :w'Xsun J]do.,VR]ke!sݶb@5y P y689ܭ 2AI"۟W y}{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺOs>=v'r?==m[E}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺[EEd)$:JiWLṰ:C=28dwHܬjz({kzfa+S-fcdI%HSy!k\[촖녓բ|/h-^nEMωA惂 TlJ:H$lGGPJ:Ax̬04 8<H*J!#?>{Z׺u{{^׺u{SlG!W7e2lR P#z"ZFu2nN޿!1QQE=-p[xQBǂ MX㶎sQPw.5uUC:<: c۸#,qw-4w6̭bklk#eHr9XQдʐV:1>r1]ӳm7^QQ]F_bZY)"T)\.xPM6϶<ȒR%k7@0H< ]Ar2pYO3K #hij#f?#cz:15׾]κllR'wXϼpȒ%[䩣AY36!\yx?c C){UݡHMₑƱsc@9#8D)Q%X^9cC$nlAnr!YA A .CB##ȎU׺uOJԵU8>:VVU"5X6 3G"1vrkL:vԀ񤬡j{TڥܯiMV(dz(W@/)h.߅~dTMA. J|<%RY; UIUu%XI;Dŝ;m^j<P2i"2]YTp1QPy^N4;lw6=tQKodiz\*~*1]!{X'nm"FXTz. EUɁtL~{ߺ^׽t?۟pkIg/SE_}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{G,3F E4RXI"6*A ~ǭAz$[hs1TdNSi+]eSи^L,N6ɷ\3RΣJr%5q.ovn>)>U*ʪpg]^׺@ A9쭂z\&uND( ]FFKߦfк}72pVEgGP2.Gp: {(G?j=u{{^-]5$syQ*ZimtpG[LCA [_Cmw-|G|)n-d(*ݒ> sDN (@(g&cc> ޛm$'{[nG{ <~pg."Iʋ,RF$r))$nG#܏ E뗿u{{^׺I?@a{}M2ZEܰ93}-B/HaD>l]ɼYj)з=YcUc?C0&eu/ezaPjEH(HaV"@?ys}Mt"4B OA[ QEEG$IR=tQnw~M R;{Sӄ@>8q^?J}oVrܟWͶ:>Kзjc5j _Vƣ |{o޽{{^NuJ|_l}OI%^k$e3UWN7m^"TRӧFDhognw-I;X4ֱm5׏|uTՖfqQͺr0sV^-mʥ撪%f!|WFF0ܷ/ÇZOt9ҟr-u}\׺u{{^׺u{{^׺u{{^׺u{{^׺Wb5#>E~-򶘔FIO[AW&z~gz'YZAfWU:)E |P?lXpE7?xキ$E* f 50f4U" $ՕhFjM44ͮ-g<,Ԫ7ڮ]+Q4f\)OW+Fn*!b J 8 *G\u~{ߺ^:ډEzeE>;'iMECM0xSKb,{1Z.S4}-pJy" >o]v&פ+[mۭ6 M= Ug}YY$,DaM6ѨD_E+&͉=.}鎽{{^׺<UA=-TR%=M-LI==MЊ~.-#2A"%i=>9m̂=ׅm*ymɃۙ `"fsv(o 8?op};OV#Dw46{O_q*՘toӿ}xEe, )}a(w0H ҏק"ܑ*OX&=G_%!Yi ?P[hkXեXܠ%kǛ3S,ƸOϢC#{{j7_~TO]'yv7d @ߴQwOA{oi F:x U|^+~SOo%j,ȦCOMU]oy>ПmtOOOIT԰CMM$s8UD?43Iqq3I;1,}I5$IyfV5,ĒO̜{ku~CZIZY)IOU QEYO"TQW7*hjIc?Ai]uj]A aiOXUH=) ~4j#SaP~GӥWٟ iRÞ#Q<(~yZyb)#CV\%fAQkhWUb(B4iRX >ЧuoO'8^u4PM7(c{QjB1FҵP:9*FvnoIvKu+Z;,HƂr_Q_Os>=v'r?==m[E}\׺u{{^׺u{{^׺u{{^׺u{{^׺Qlmݵ~ USq&۔+3g)TaRl!P]S熳^I;MmWi%DVhHu!vD ot^ܰߗ~m{ˑy [t+(f(bFI FN*m{ NSxb,i.aH$qswݜSeSv7&KeT%Tw YKrݷu+g2l涷6k=kN*UT :=<ϴv Fn,ZIGC 2VD4mqq}+䜣0?undt޹_mܦۮ`K5tPblE4:I_ky6=ݽkk "i%xJZ.Mi?㫮-ڛRy!1|c:G3IJi=79۶ns_9n\ 6NQZh{4YfYt"`:W"yvϙ}wyvoߖB3w1 W(\PitJ,rwn榧i-WarsY"?m{u{zX_ouaYMm2wyES@>t3cC"ʵt=k^()73垢ꑤo[7{tpp\rֶ I`-zY4SN>AvxnZfJ-U)`7*ifg&)M4)[&[hn 9Zdka ~}A&\V4?*ty{Z?Jjhᛯ>2,S<f0%i, oٻ>?|V>g](THV& /:ɎxwشXPFO.4 ,$Ruһ`'Y*C>2:SQM 'ZL!".?V;~Ԭ?yuyr4F9gC1XZʡ,FGG|4vyxn)# %[C%44ZPB>|tɺ6©<_?bVrodr{V*&KOUS8 f>oc97f>d~m7{M`Y%r:pRVFa=پvۦxMs3$Eco )/fD;xzm MӗO}j,ƓZX#=ɞ?*{IwbٹroԖ_nn#Hݢ[@Pjqo/&s4߽0[%ݪC1ug,U8y9u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^Cۉ0#fwu;O|)|LIRhAˏdý[ܷlHt46j}˥Vѷ̏G͞"$h-hA@ǸOrzXoz^׽u~ }#fw|AX)+p:9URnʗhV>XTOiS.w_( )#!ozY[~UaK˕ я'7@:^׽u~{ߺ^)a))i"I)CO VV06>Ç[  Z3f0Qz|y=ʜC{?|zn&} @%/8?FRoMشʩy^e\,TlB:J,N*,K$r!(n$Yԫ (A G<:efVRpADyU׺u{Go~ǯqI$P8׀ښm.mߴ 4]{[׺u{{^^m(璕9ܰ6esX)؄WT^*(in&H\3.n]09ȍO]@`AӷEp$iG9a(XPm SRLՕs^O/#|RK5Ed(HQB"hIibUTQEUU_ECIJj:g{^  Ӄ`P^]^nǷ?֓$_܋}\׺u{{^׺u{{^׺u{{^׺u{{^׺Wb2l]\<]m.K_J:*㪣A}SDhwMne,o-xdXeCWFeazQiwuawke;E{$nOV_?*/Su;+i% <.Tn1[=4YrmM-9 -9!!-guM2[ $K[,[4*rɯXy`#*۪C/a2u+Q{|)3=\UO-MUTTTHSSQ#M=D/,坉%}歵Cg kqDDPUU:eYygس3319$I'=Me'pTZ.[p *1uWӀH:Ih7ݢߘ6-tFJkTvJ5rVPF:Q^ɶ~ Mm˅ᶵ^q/ӋdI#)0rOpS_d$BV2'ӳ +#2@Ct/d]JsuUuC }^Hץ[+Jwf"6.G`ojy3^a~rn"8YkM@!1e'B*@#7rygnmo"5RmO&Hh݄~m>~Oyʴl1TELByct}˜N^YwMQ[O@/ ҍjr8r-BLOC+czUٙuXmJerqM!4gD# >]Isp7 [(gkv聏G`18"i1Xzlv>yRDDǗKIeIjĒ~gXߺo{^׺u{{^׺H A>׺,[R$Y}Grd6kH -\KIvJyΗۛhY7 o! 0aVR;(%<f~BAV0 WgA4rG$P)fTqHUtab=_myʰ `H#%ukqe;[DRQ|Aeܹfdaw,|gFIaQ`ҕ EAFiιDZKHӸ59r׏~q)uӸ59r׏~q)uӸ59r׏~q)uӸ59r׏~q)uӸ59r׏~q)uӸ59r׏~q)uӸ59r׏~q)uӸ59r׏~q)uӸ59r׏~q)uӸ5˞poyx?$I*Mэ(JJT!Jq1wMn"HF}USU>b<"c%?MC榨b<ѵ 3,B+c5Z|/дDGW4(~ξ;5~>Omb2co1ݭ /{T}1*Q'Mms~=7uN{{^׺u{{^׺u{{^g;%]v㰔Ūvg;[%^K3ˆmUX O6ȯjt=r\߿r\D_G{t64>r\߿r\D_G{t64>6]ep):sV UKr)JHslϡt흮WNS*̀>}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{ιUV<`ZM, /_Y%{m1(!yE-N J~}:ZXhiiũऀHiHb\A'yj+,XjGzo{^׺voՍ,usEb=K8XqeMr)p~go}oqč5yȪ1owi":bq#^GPUQTDE "DQ`y?]^׺u{{^׺u{{^׺uwn\]NjgB|rYEd'X*]Dx@Ѱ8 >cúz{u{UwRqU2› IQ!uA++d[kRaj,1J:Ms_U+kw1ԟGAB &ғ-,IqS(*R*ԏ*) f6;ݬdy0UaUaRGA˻+ Wpc0VV0OS}t{^׺u?p:Yp[mwm Zd9Jg͑}qf5 >Kf7nܠh՚" fEbJ+NQ?-&w(iUu1h 4;W:L* 2IHf7Ut<lp9GxB*=qmqi3Au G0P"*W1 $(Y]"$y%F qƥGbIʯ#*FbTpdՕYU& O>g,Vz1u1z,eRhuE S;VMy ו6qx* D [t4vfzxL9s䣣)D龽{{^׺x۟8pI?)o"j/G_}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{-FQw~MAx(?3q;۹>='"kOJzAo_O|a_SZàW't ׺uVU*kKIbK6k*YEյep͘ Ks<6.`=IgѪݙ>E7dgsy( <9l>{͎[حoeDK#eni0n.ۇB.g'׺u{{^׺u{{^׺u{{^׺Ao>{LjKtb_7?]-4"jwm{W,տ iSO)z;H%9Ƥ??RzR2Tmȱ&i1Pn\0Dte$Ne1bԳ\b>5(ެ&cCVk ۦض.*{ n>3ЂqD{ߺ^G^t]vS6x*FD}{r8::_}sn,l:O`NP> )y 1nen`孟>w@t8đ5S槦LƵ4d*~YS槢mmێ\N^]fhdy(T[{"hNe%]?Э9{rqٔ|5ಯo ~5Ag մ5R%_}U)dHkc6dc6X0sg!)<b&qtrd\9)O@M\ٺÏ~Fr>\"z2->ܦr r"z:_@8`@8׺u{{^nǷ?֓$_܋}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u~Kbx u~op|fꈰl5gQF?5<-{k[mld?h軘& -ڴU\SS_qGA{{^Mכ\]IO<~Mqg&q NΞ%t7u $M$~>]{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽tvVŋ~mע8)rj Q5 veb&?Dj6۽pUC2t2F$7 U d=}E8:jeZy(꣒zJ䨧#oQVB:n8#{Eû_mre>N0iJK $5*p|H2>{*^kKVӯCy:iBM_!k a:v;ylczްq0$qjz=tM÷0{>qcid0N^7&x^9c?IsG$3F V zv)4 PA}:˃v"aI%䞢iIeIdbĒ}#D4 (,4,W? `0:vn׺u{{^nǷ?֓$_܋}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺uNލE]xۦ^M3mW^aY a\ߚ=kRU C|D cMt,-rT%?_/mEp0ƱC q H,E#E=᳻$ZF$xMI?2rz33;.ĒONI?i'u^{Y V9"AM=m\$T49zR(f;NunV[UVyx(=* Hv|XUtqzf64xɜ51K>ȬmWoj\d1GNOڶ]mڬ-=M8U0x$V,J?՛OB~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽tMG 4MYW1M)g[Ո(o$78vskGZ>(O΅I7mtDf qʺ~{ߺ^с\$ۛO rLRq5O9'`jF~ݗjXmSz'y7{ߺ^׽u~{ߺ^׽t?۟pkIg/SE_}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^l$~q;QVrM:*cpLtV .>>R5DERdP2sFFtGdKOS抾fVO?7=kWjde&1e*#E JRPQT .nN"?2պKߚ i1ƕ¯Yd/'2FAI15OA׽u~-o Ͽ㭨U`-22JՔIDIP$}D~[#$ }0ea(ɇBNLiEJ}GҎ{{^׺u{{^׺u{{^׺u{{^׺u{,Ur-r&B;œ Agۏ'q|K9RoG~]z/w|’?_W^_x7{^׺:7"[sᙂöqu?ڽ_>:O<__e/mvYe_ YU~Z3Ѫ3^׽u~{ߺ^׽u~'*笠mj.k"-^1Ũb) }xmxd(u#sOϡ{ٶ۽;{hRDku| ]#׺u{{^,'+,fGIs: V(_X O?apE#|&T,6fvnϦ\R5jm%Ѕp!?Ϥ5l KB[n-Yy(Lk4'xǥ'-g6O=fr׿uYo?G)н{Q[z-g6O~7/?o^ןex/Bޞ3e9Gmúz,qe?^fl({w^E3~l' ׿z{L͗߼ SdyzOs陲y=[8Ql?/^o36_޽;??~6_M߽=fr׿uYo?G)н{Q[z-g6O~7/?o^ןex/Bޞ3e9Gmúz,qe?^fl({w^E3~l' ׿z{L͗߼ SdyzOs陲y=[8Ql?/^o36_޽;??~6_M߽=fr׿uYo?G)н{Q[zcH#qe~G#P6O~3/?oU;v;f&ye+jich]=:$|bV,SxVlZ0ե?V0u= nNuen̅%E!IPAo? kR'ý~{ߺK>1ufH+z-U%Nn'r਌rucxZK>{_=ieXg}'npq}%`ZbBH28#A}ݣz-O15a^Sj(0Z[Jd$lAc6J}/AI7t"v^VY(GUw-g6O7/?o^ןex/Bޞ3e9Gmúz,qe?^fl(tq{cmŕFֿkɨjMs:=Ρ,Wjљ}k.,>r Td%]UuFfg8Ccw= .E79o%mpѶmZmWRD5k3]|7mPd=r#|mɷD%q[ۊ-5tçDA Ec+ͨͯ^xTZzƑ{A^YӸrtFl[.4;75/$?#n]Z Tp*}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{TBɱ3!lkqn[F?V?#kK3oxEe?OM lj:6}==Ziv*mwCLpjaJ/U?Bo63Žew{^hb EƯR>z'^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽t_{nI&;(YTQc6IYꒈ 0!6X}}=^Z6,A Qz{KSj<Qk7`Cee!+ 7= "u~{ߺRoql[Bϗ9)y-IsS-akJnb=rVFD?lpWZ#K][UV=2A~;[yK-][^<0Ozգ}fG<{]~9^l4X t=~COGfYVkO_u=~L)OBӃO׽u~{ߺ^nÃݭ'IOO[Q:}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{Ӵ6-n)qy fS dCYI2:T ȱV[\B^b =e`*U'P][\fIM@VW+k:W)*)+!QOO4EখHci*LA5I]U)_*ѫJHgYMʂiR# | y=XrT4y p eݰ+d(c=AQAނWƾI8KlTn՘wPUdn+~Wƅ]o-ѽ(jxTu{{^׺u{{^׺u{{^׺u{{^׺u{/a3t6Vwh~};hS=Wܗͷp_`ow07Am? scײ~{ߺ^V^:)5Scx-5fnPO2F%BjxQ bM޷.aخ䷼-V kvbfKŝBye" jGha,Z=h2K4qPTIfƫ9UUK SJ& &  .eI&85@ASZ(ۦ:u{{^nǷ?֓$_܋}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^}C?{ZX+w>% ?wo :tDseD-XD<~m1g~`3q1LHO7'D{ߺ^׽t't=7Z3bx=n#>&Oi*mʏy=+h~נh> 6XR>5ExD'Fܽպu{{^׺u{{^׺u{{^׺u{{^׺u{uOgGu=W^OIz@׀!ʟ)_E o;f??g{UbkI,u朵)Dw&Y~I j K!V_Usm6n%ePօ p T4Kv-b{ه4@4i\ҝN 槮}a](O{x䁏H&ܗ~6ҍiF !"59euGwGmN!V*"#(" cAobSJKWGY6ԘR-qX+kHZ\GKbeķ!>ebqoW'GFO܉}{ߺ^׽u~nA۸ nbv/7 C (k$earvysOf**j58 0:O3K$|L! <ݺk{^׺u{{^׺u{{^׺u{{^׺u{{^׺ߺz ]kZKZ<+3[tIb8/N>=~{ߺKRc G_)i{S%WSA[EI(Z%O%Bc,lf{ٍ͢jk 4(Omxz7r]Y`H&"hG⍍rOUTDR8cB"F@TDPI$ߺ^׽u=YX$e#LicS=B5<7P:7Ero;4[͛oFx!s*2zT7i3Jcq7 - ^{1/Os>=v'r?==m[E@sb䈿[~m+L ?sb䈿߿v?na׿??D_Y߻m?u0{Oj؟"/ݶu_ۘ遽u~{lOV{O:{?Z?='H=mcWnv`oi]{$E՞^s07֮m"~iGXۯ]W^g~m׿L ?sb䈿߿v?na׿??D_Y߻m?u0{Oj؟"/ݶu_ۘ遽u~{lOV{O:{?Z?='H=mcWnv`oi]{$E՞^s07֮m"~iGXۯ]W^g~m׿L ?sb䈿߿v?na׿??D_Y߻m?u0{Oj؟"/ݶu_ۘ遽u~{lOV{O:{?Z?='H=mcWnv`oi]{$E՞^s07֮m"~iGXۯ]W^g~m׿L ?sb䈿߿v?na׿??D_Y߻m?u0{Oj؟"/ݶu_ۘ遽u~{lOV{O:{?Z?='H=mcWnv`oi]{$E՞^s07֮m"~iGXۯ]W^g~m׿L ?sb䈿߿v?na׿??D_Y߻m?u0{Oj؟"/ݶu_ۘ遽u~{lOV{O:{?Z?='H=mcWnv`oi]{$E՞^s07֮m"~iGXۯ]W^g~m׿L ?sb䈿޿v?nawWrʖܰ}-u]<C%|qAPcUV1I.~\ղnQFfF jc} wܗߺ~{yy?aԕ h/rȣ06*RJdH0}7jm׵GC f2xm۾m|66\ݶu]ϐ/i֮'F~5\['DrGi ӷV.}gs"08aBK R$?1 }`mU|vss!9Xi|%Yb})oWٹCzl6bqg?N?nD9b]h B+6O;n~{lOV{7iGXۦL ?sb䈿߿v?na׿??D_Y߻m?u0{Oj"{ₐA:b[9:?>me+FZ*n`A+)Gtu6dۈ}!6銽%\]avs %{ Ϗ+(QR,ҙc-;N=Jvi=.a65>k+k^,076sv?.sɼCՙ`h6ic7р+o)9$!䴺z%ch`olI\g6jwXמ9a7#տWN=w.V9bTT*VX"Ãu; 2B6=pqǥv<}c-#M,I? ,?m'zO^u^ao~>zת}zT?{^S׬?mzׯXAߺO^u^ao~>zת}zT?{^S׬?mzׯXAߺO^u^ao~>zת}zT?{^S׬?mzׯXAߺO^u^ao~>zת}zT?{^S׬?mzׯXAߺO^u^ao~>zת}zT?{^S׬?mzׯXAߺO^u^:UQ}<}XڻN|ǣ($Dzڟ:+U^xM+pI R2ӑ6#r0z:68c&(n<4Ǵ.X{Ƕ{zת}zT?{^S׬?mzׯXAߺO^u^ao~>zת}zT?{^S׬?mzׯXAߺO^u^ao~>zת}zT?{^S׬?mzפ[{yscS'ZjUHWKC4uSTtJ\X${nXaxM*)TB0N<^&"FAF0Ezxbi1*Lv6HiT$'Ϸ:$HcRI'zao~>zת}zT?{^뢪A?PGJAhxt/wgWmNv۔:<D*mޑrVb\(h(,~o68 8lmpnri76v'2J1r>td%)%<ܖ[i.bdJ:l?mnǷ8kIg/SE#}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺dѣ31}?goе_E=%b>n.A.olA~ڞxyTutC{.ޑ l0ಅ go~[>ٛ G{=X\EKؽ}/9.i| 0fMXϥ뙝{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~#*uj_t}o윁ɻ?6ɲVw{~q%ٴI/ff˲cP˧Hʯ'r)r]{){̗ss{'OY`D_P ,|OimcUB63jb>h(flB8kYcy C)}?AsF[&Μ7h"'VbٖAm 4QPbN-7s Ӹ7iw (|Yw`<>Tkj0\V2ciYWuOګno{k~ 8gur3.ͺôZH$1G鼱O6UӕNޔYMۙ d}-jLۃ !A$NJG#-UkO!kqrPnrDYŜ1pKxFC:(cB4dܭV׻sM2Z+Ca3YGM!.GC &俽O>sowͲ L.A_M vע0I@B&[{??,dfR#xSGB4j$А ׯ{^׺u{{^׺u{{^׺u$ '$^+rTm ųi(nsYhbcn5 #HK=C/>Wm-wOUE-a4k ?j;pϸ?3{?^sXg0nT[*m \:ke=t0O 4OOO T FC1 PāUG@+$$O+<řՙ$OkAk$V""*"ª `;# +krԃ1GAfG 5U"3*ȕ[}|"-Sq(RMbU뽤sO\2z!BŬ%[v +%0Tۡ.pH @=d$t6#.K>"d\8!F=!B}ʞsO7ݎDߞ]~|%~@IX}{}y*E͘ H!E3GY)+)4 6Iqj#o )A۶X_aF~ޤ{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{ÇZOt9ҟr-u}\׺u{{^׺u{{^׺u{{^׺u{{^׺uΠ '`0{sVaER&s=f.t$#tNzC%&=?m7lnd676NVH\3BYRYx2sk/.-R+- (N*TfF3xzSJmQ;۪mr uej&`o|'bLqVSl\Oڠ_emѽ"}|䶜Ƥ`+ݥd7y^65ۯYcY5$ ÒF_^ |GXQ2:;=_0&-Ym-?XPML[C?,a驱@OV&b@ނ/>e}ovDߣFܬٯ DnRhk EXmJ qL1Oe_0^s.6 -[i6heM?{/A w-oji4-­r ~2z繩*GqSO-5/ɊxHm㒒9]z9)^~u]ѣ0 BQe.G&6ǒ.ho0/nA#bPt);!I jk)qErC5]QLYJS*C"F y {}vd~w[Zs:]$VY$ (AE,;A=y~A=4;$VR RUh)(N]}T2_6JZopcY*%rFQqTkS \{˛Pr.o@mB(;O1S4;hzr/nd[0KHⵜGOi^H@Ad+挵5rdYrYڳ%2T95yy=oCacZF(?t< 4 /h:3<7/xY/'թ9~s7׺u{{^׺u{{^׺uVVQ z ($)ii]ROQ<(ë*ƊZF I'2I<IvPTGoùF3ro[KUsgNP|Y |~/y;9'Z<6!psG㷵_qǾ=m2d[#9& V[~٦)iii訩iiPPTl\\]Oww;w+wv,jĖf9$In۶Hx88T4PT0LtRm,O VTG` W4X^it33Z:jtyd!co9=死ruI!÷H'"ت/s{䏻{iHRw,in,)ZR4 #TmG|Vr=4MV&eaA,_CPҷJ+bR4։ kCf+TAڠuﯽ9ݓ1)>g^~Jͩڬĕ_Y&uѭfzSr XF g'S㝍|^_G)Ϝmpw2O:s/?gyqx2D__^6FȡoLѸu C) aj8}S@HY4g~DcO}lu~TQid1/7r&s0jo#g_Hϯ/ 7Hv"<$C .^]B{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺCG^S|n;meQw1 CS]Fg筪қ -(;ߝphq>dݭm2W-Ʃ⵷i92,Lʞs/-s5Ix^g,YjSDhH5Ƥ /z:nǷ?֓$_܋}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^O׿u76&݋i.]J? :a**p&t$p:}־Dξ1C4̒'ԔwRGZ $1ԍ{g, lݵ>~QkW46\ROIB!$I$II`uijrlV3 gesY9)q8z"Z(ƀ#$j|\0r*qLk G ,Bou >G=#}Öl,s$oouM< b{ewrD7pvTyqT55AE#P݆s[շqik˲iAAH:؞Q>{tZÑ,kC-'3LEs Hl.L]e*Ү$n|LJAǼh%*" }=k˒l\nݬ`S8[[{/[݄O³?+ T|oca[SvpQm|Λ}JϷiݿ0񴼚6xi#Mdp?Ҟe?Ӑ?yn |ɰϪ =ID+yI?Oy],1׹I?O~ߘC$uuOSߺ:?'){{?I{^^$=~cs׿1׹I?O~ߘC$uuOSߺ:?'){{?I{^^$=~cs׿1׹I?O~ߘC$uuOSߺ:?'){{?I{^^$=~cs׿1׹I?O~ߘC$uuOSߺ:?'){tAMo{*:hsw5;[IM+qW⫳4ؼps>3tolIY5tT(ϸ?w~aYo=ʲ.$cqe 1Ek%tQ>ߵ[8լ/OR;ۺ͢[r1*ݢyV8w7wtUP) 6VU,T݊'J5^cV*|<|J`};x>֓=OJzvȷ"u}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^Aܵ|U-4S itC4o[1 j+UyOkTHSڿw_憎Ov){#?O r~uv){#?O r~uv){#?O r~uv){#?O r~uv){#?O r~uv){#?O r~uv){#?O r~uv){#?O r~uv){#?O r~uv){#?O r~uv){#?O r~uv){#?O r~uv){#?O r~uv)tݑUgzL*$j#+F ;@TDQrIO8E_x_&rޛFnݓYY\eD^K6".G6~ q?){S<ϜBG0nWi3Ծ䧰=m˗=, n78]ܢ 24x=EKS[es7$uYIz ]31PG{'ǻ{9v2mҩmnHiTPw?uL=8(ܔ.H99*?qSH}Ѿh5KQ˹D+5&MsS)+OqWz} 9k`g}C}6[_zO}*t88싞o5yλ -i[:ۂA2-O(٬}2x>qzUA%4Y *?|t|=C-A8){װW$뇴򧳛OoCs- Ԡ59P"Z"Y{Or`fCB3 xK7#?O rrﻯ_'bWl9G׿>sT'w_憎Ol9G_Uj*;nz)iޒ&)&kO&sOc)Mox!ؤ9SBm*)WK+K?ϮrG4Zrg<{_L{=SQk?|跤.W;Y{cfw'vϺ`ݸЙ5ayH.)R.,UXTVZ' z+yX^sȕ[kޮ:X%ʊI]zЏ9?~}El9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9G׿>sT'w_憎Ol9GӶ3Rg,4lV@dң>~nm顙LQP~})aUԳ# )Ppz}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺uY]EE[cYfI $XB[,e>4H?9{ Ĵak$H?f}s ˞erx)4srbGSpUcGqH[KWY]J ޕQ6H(S?_{iպ=]}tqRVH1e:u>6z] (t8l.5^:N*Y"8D(cH$X(,qEH@ ٙ䑋HĒI$rI'$NIT((!E *@T 0:rmɰbO{4D(z]ەQQU .~CxnJzi> М^W,TJuoWD=<ْhshcvQPRW\BU, {7jdwSZKNVid13FmP yI*!nb',yc$j|ږya:llv;mloBHƊ8*">?0ͻ|ӽ]n;܅游GlѦbm O-~/zfymփ%iU׈j`T?U$CÁ27i: {H,6mݽ2!e-TWH#G}7W\ڷ!gAHҟ>3˹Ayo,:vS_DOњJI pm|׿u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^nǷ?֓$_܋}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{I}to\5A [w bNlp0dПa~mnRM^o k :cj;VI[1Uv==[FD}0B2:zޛ+̢3׵}sOa a\L.vjs P_4U4召@گAl[KXs'?x(6d%KeO3| q*j(DBY[JuOYW)晞W<`ys޹wݥ5ifr~BUH(|ɜeʼV[O.[ıF)sr,H * .l<dV&yx< MDPI'I$=$p;h|K 0q4UVpUɎhJb 1K>|:ɱ2;Vζ6y |"|TX2"Zrg~ͼ[2l)_jZX3"p6eeWd"M켤8)P,+)ǒ5qajjX $;W=]5X< `g\)nc& ö=ޑk42E?}wCAIFhqQ(IEtS J=ܚz,KԓI'ORu~{ߺ^&Í÷3+ٲ|:&uTM(Gr sS#:ԫUaF$tlܬ)wm2J8ԏ`Jm}˳~a-U'ǐjX%  7μ< <’0C_:A?>sݚp4_d1׻_2ċ鬣B?{]]mwkW?|dW:'ӕ<)'yopGm#G:HGu\=v'r?==m[E}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺i{vUg-;).RJ߄g$߅3!r%,MRN71YI5܆;<ğ OINc9[;5.ڢI/Ls?xՇyhyM4%GJ3'(#Ӭw.C6i$K}GNqus5Mjg vpXkQ.F}O{N}.,jej3PX"?cr<Ϯ!+Yoow\߿%lV^7N%[GLt!ax]@qђET$(i>c$M{9pv[OYi\9$@(uy[y/fN-`Q-!W5P[ՍX\{Rܹ^&:i!W55o[]) r1?A_.3sumpV'OfQGϢw {͓j8PTW`yFO ?`n ΨFͬ`|*~Qa3n̪ϼOg2W ?/4?3}}~n>s}%ݳU_ᘫ>~<OېOJx" z~C<`0C*x,vmI$tBv]u#zH㯰OsZ.>muKnI[ZWC5ˉsrMVџGrS>*|?K{WOP׳(?V*FnI(޽{{^׺u 'Wifa31Y#HwDx>ѱѺ_Du7`7n럛|O.^9 \%z IPO :h$ . L7~AV7^#CI>ё]m (kk^;UZXL݄ :?~7]d.lR$q&p4zD>:u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺOs>=v'r?==m[E}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺uyul6!7]E.&Yiy姁$1B`Bk$Gm;..xbv^C%PTqO{>pLTEg$~k ]u`}9bVl2Gz~޳iߙ/pk[R.5,Go?|x7kEmўiW}d(t3O[pccv@>/n+1[s!֤|f$37ۚ&?ٴ= m{q'A _d7&mu {>Ҷi(娨8Y*%X$yfVX%8Gc-+TXTdYd)fTUU,*YOXhv&#YZ^,^Ч3쒭bߩq_'O!cٜ^%`|W#\~5նos_6J]Œ1IoYhp|#;6A7]A >f ~UrϚj81{H{S rMo_FBy?۹Yw/@E⽘|CO.~5^+KEŦUyڛdT3N$ɽlvkHnQ"A<ۜ9s5IiC\Y!Aғރ{ߺI5׵Gno y~;ޗKaϽv?QNٶ>ˉ~U]q1Il`Lb&֖ռd‹|1˸{,+or8_GiW{ߺ^׽u~{ߺI(AM˳py迣mv!oeJ|O, ;')\ۺlח+ %;ZcoVb1$.z$c7t?۟pkIg/SE_.=\=zߺר}^CzǿuC׮=Pqz~>\{^=zߺר}^CzǿuC׮=Pqz~>\{^=zߺר}^CzǿuC׮=Pqz~>\{^=zߺר}ImÏ} smIQ2d|8IAfiHlm[’ÙH؂K ,zw?H݁R&?8mJ~P\{47<'k$+uaKe>c[1O_C5eM jz3KSE12"},;mВ y5[Yl, O^yogNd m&3\ck!x]h¥]X[w(Pu:#Gz\Uh"EY3C$i 4I7&o+.`n[ݵ@i'Ki53epY{vg[Ͱs_3Om65eö*<lA!d\{^=9vcr{-"/8Y䂮KUAppT:Yk_~{|uˏnWM*,R'ǮI#]'5:W\w3.״5PE\{^=zߺר}^CzǿuCq76cnmh▫smj ppg'JM1FmG F/opO+.fcۖLM4Go<25i]R)´]yy_/ks=o#o݆b4HRI fWiZ ?ڟ=y >Jiz}?Cd[tכ2=Y$1KMPS,7j"b9P׷ɜܱ2Y Đ!T{d cpF445|ϒ\{^=zߺר}^CzǿuC׮=Pqz~>\{^=zߺר}^CzǿuC׮=Pqz~>\{^=zߺר}^CzǿuC׮=Pqz~>\{^=zߺ 6AlmԨe,*׊oedwlvu[eCW٭ǵin&zZrFbQ1D?0[>m~0r׷Vm>ukc~7+Gekp$V8x#gXұ>;|˛f3ʹhosM+O4EY٢d`B:,*<*76}˶g8奔zm}ܿ(zDΟo_}={l>_={"d?O7oE[ow/?2~7^[-^H~QaygGrL?߿}M(׿m9G׿&Ct߾Xer!:|q}S,??Q@>8奔zm}ܿ(zDΟo_}={l>_={"d?O7oE[ow/?2~7^[-^H~QaygGrL?߿}M(׿m9G׿&Ct߾Xer!:|q}S,??Q@>8奔zm}ܿ(zDΟo_}={l>_={"d?O7oE[ow/?2~7^[-^H~QaygGrL?߿}M(׿m9G׿&Ct߾Xer!:|q}S,??Q@{"/|$h_{奔zm}ܿ(z)wM=qa萬+ۊجTtݎ"꒤MmoQS3RXr-Z)m#4NZNX〢@: 5Z{uJV $4@^M?+ܰ#<9ߗa>aޮCD#pQ՘RIt2L?S,??[-^H~QaygGrL?߿}M(׿m9G׿&Ct߾Xer!:|q}S,??Q@>8奔zm}ܿ(z%4jwqSܹ LP1ܘq$Ļ"DZg$o,o ",vT0Klܱn̷P.%pڠ wVnWvN܎S&R-!J茲 5i·L^Zm__={,~opG<,+$?":Y/&[sǸO}u7(5`8奔zm}ܿ(zDΟo_}={l>_={"d?O7oE[ow/?_LV錔sc1TwάԔ!G.FG {9FpƪnT ꯯ϩQpt9"#Z:Ae7GFSv" <}dsLͫiZ)&c_UJȘ {78QN\e:yy>Ϙw-{ t' k (jEqL?=C?er!:|q}S,??Q@>8奔zm}ܿ(zDΟo_}={l>_={"d?O7oE[ow/?2~7^[-^H~QaygGrL?߿}M(׿m9G׿&Ct߾Xer!:|q}S,??Q@>8奔zm}ܿ(zDΟo_}={l>_={"d?O7oE[ow/?2~7^[-^H~QaygGrL?߿}M(׿m9G׿&Ct߾Xer!:|q}S,??Q@>8奔zm}ܿ(zDΟo_}={l>_={"d?O7oE[ow/?2~7^[-^H~QaygGrL?߿}M(׿m9G׿&Ct߾Xer!:|q}S,??Q@>8奔zm}ܿ(zDΟo_}={l>_={"d?O7oE[ow/?2~7^[-^H~QaygGrlad$#8|gpђnR*|0 ϥV^J7ĕ o g}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{$K7rOtJ9dTz tgY~ahEUOWoPwdl=$~zrqkƵ,-u_'?_s>.?E*2]WZ$I$<׺u{]vHs9QԻV_--N_ ZXιWQD"TY.=O%Q4 9[vqy|hH>|J;soU'_ո2iMG-ecuQCOFSM\jR (ykٷ٠@j5#RA"}:C͛eպ5" &W=z {kKw`c[rx?SK[y_HGvoa}i}߰~cl[h S.{wm۶FG.mQ @T_TE :}嵦uO#H~:9l]iP ԇC#xj)()"`OOzQiu5v `¹V`uw`sisDcFF#[҆ccuF9anai>c:|c_<|z>%KmϾI030e1T{SI_qwQ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽t?۟pkIg/SE_}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{¾H6ƣmm V3+Uo]ȶGTאoB?h?z >'{èct05͞ʴ ?6'{s[*;Q rm8gf?@=?q_QW^׽u]}an5xO`lJUaM^zuJe#fm~_M4Ud'ܭ\۾n5MxMEBg A:jM8ésv j":x >F,Gr$;fbYI>x ;{hU-QUE}UQWvck6GcGCSMuu(:]ŕ&Y Dx)}Bq6`Ւ匈A„q4P<EhgEr4#5^:$GAcwg^^o wLݴC$\FquzXs5n OG^jONNF-9 5-ta~/(beLE[v}U\:1Nܨ@IXλwFpK'ğt }?y[纜&ףi{^׺u{{^)6^uMMS  LeA iiY<(ᑘnn," FK,/ۨ$2<`_#[~:4zt(lU#'MlT73s;DؑAI$P4& vݣt? 5]:u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{ÇZOt9ҟr-u}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{[z+B%*py3X+4x{id\nPI$]qkPq*†UgBY"w1s:d*Ђ7CCvOR6yqjqtP}/QHK,C,-‚ơY2*) +RjM=z3in 4 5ҵ>dS:׺/{V{iǔq'4)`QV*AMP TE} ),4QhE8WV[cD#: gwrlvcc2mD+CtsAWRt/HQ ;G#1bAYʛ|]=휄:`0CZ4Kgwnlx$ܭOҼWZ㢹:po>DžyLl9ifi&|7jj*ih'O=cբFV&M9 oܶȖcr=F?3Ph)_ϩw;mkO9 CJ_S8zǬ_\u}Qj+Vha.T4Of$17Mx;`8* ?՞xޮA'ϧ׿6nƁ'ݛ2zzZ*?KLjEL/ yBLx*ۃvV#D`}E7 -3Yjm6ۆTS,| żmv> #Zcn GN6s.eJz,;ronމVغrJlKU# Jjeq%]\1,Gv-6^NhX)$Ƽt':XYm\5Ufy}zHrybvMj< SVc4Q MU TlgsfR9C[̺qXVpңkkMox\0Gσ8/+6/1n0tC]YPxd@Xcw=zn#jQ>c tn6٬r&_&o5.}迯{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u^U;;%CvF*{0pf^C2M㞊^ij3$D̛׻V?yi6ǘ,ma#Hg{]^. kǏ}\׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺t[ NG5^u]Re4*熝Ғ&i  =ðŊnɽZm

}A G>7$}Ntvs۸-|]u~^o-.bpݫᰪ£ȹ%\}:)4V$9m˸+~W?Eu+,k@)ZK \3#}UH&ݴۀ8aG{?UT S75BS،k.a!l !.?Y=4ݨ?]cޒz}dX'LkyO(uΫ6 b!/ϸp奜=:-vK}9jpQ_Ϣ3=gmJG#<$Hw] Kvi題 ,J&R>%sY٧}[Jzo3}+G_FOȞޱܩK_U;y n9 4\z_$/^}HT{μ7AX;K?28:s6g` (޾~GhXܖ?3bk c2TWS8 ZC4l? lT# A(GP\ VU$x8T׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u{{^׺u-M{(cwll16+(Ja 5>3wǦ y/ly& .?y[Glk&:5]=B]\˂8 2j z]4xt)mNNMh:[&tcQU㱛=iLB+*#I0h~s9/qi=?7B<]Z`f 6kh^H-U*TmlOoּ[u svws٬54|Yd nܿn%f?Vc%<("*MUm_<:}\׺u{{^׺u{{^׺u{{^׺u{{^׺u.{ ׻4cN͊lzcqCCNusOR+v Bw`}([8J!r(&?3 PM=>_V%v4v^9EO )Y.WrU,(QR7 grF2\I R8x-դeL,!QЃR?܉ӷOXq>0o:AX(jxڜv;kj`%u*%6s 09 93m޹uȖ_;\"ݴv[_n7 75h-]*Y̯X*} Ϗ-Ø! 4m+ݛ{h "Id5$acAߑ[StuNݮ>ݔYIz%r4צgn ۹iR3QLIէt`{UJsv[ueNcit*{j\C8JQ՚>kd8g|9^f[6Y^M H|b0 G]oyBz7GK{ĵ*xf6W\@NoV{]w վJ+$ 1ui JS6sSd,Vh^|T)>޷9͞_yCNQ Y/ooe/- 0Z"ȖQM/ %j6opz[m緊mu-Y&ԩ5<-˃;p熢og3 #MO"+sᝠ$Γcܳv1:Ynuj)2S>F c.Ͳp-.ep->DGUcG]չH'in R=aĈ T0)$+|C*"y`خC|!OTE"RV(N(bƧYte(@,@"s$n\YkCcU$1PXp>c^cט&響 y=)豋=Z U )֥hiLjHyi9}k"6> v$'k@:}?0Oe-@Z>WSQ $Or:fP̄$~A6i]G,~ "8 ^ΡmAY!۸cLO*CKX˚eC}9|ml#q5 "3L\ռm Nz?8|Ւo^44weR \/BWf6+\ %z-!?2I y/7 LjMr1A?OS3~;ZWWEͅ&^(bH瘈GU݀ nIv 3OLc ^V`klHEHQ>OAP@ {^{eT]HsXt']Q!/Yk}fgZB)r?8 c˺.M"N8pCEǵn2H!$zjG5n9,C̕^_RI_FV|4G| .CV95lϥpVܬ#Qܣ?/QNJi9iI C4Dʄe$n=]D$%XЃuߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~{ߺ^׽u~