(A) NADPH oxidase deficient (phox91−/−) mice show comparable reduction in bacterial clearance in both male and female mice (n = 6, * = p < 0.01 vs wild-type). (B) In vitro killing of pneumococci by normal mouse female AMs is inhibited by the non-selective NOS inhibitor nitro-L-arginine (NLA), but not by its inactive stereo-isomer, nitro-D-arginine (NDA), nor by the type 2 NOS specific inhibitor 1400W (n = 3–4, * = p < 0.01). (C) Female AMs from Nos3−/− mice lose the in vitro killing advantage of wild-type female AMs and show the same killing rate as wild-type or NOS3 deficient male AMs (n = 3, * = p < 0.01 vs wild-type). (D) In vivo, absence of NOS3 reduces, but does not completely eliminate, the female advantage in bacterial clearance (n = 15, * = p<0.015 vs all 3 other groups) and results in increased mortality from pneumococcal pneumonia (E) (n = 12 female mice per group, * = p < 0.01). Conversely, transgenic male mice with increased expression of human NOS3 show enhanced killing of S. pneumoniae in vivo (F) (lower bacterial survival, n > 5, * = p < 0.01). In this low-dose inoculum model, NOS2 deletion (G) or inhibition (H) causes reduced bacterial clearance in male, but not female mice (n = 8, * = p < 0.05).