Thanks for the advice. But I'm still looking to buy a -new- gun, and I know I can still get a very like-new used one. I am asking advice on a good, full-sized (I had med-large hands) handgun that won't break $400 dollars. Would the Mosquito be a good OC weapon? I'm not planning on going down to the range all day to shoot, just want something I can carry on me that I know will work when I need it to.
If you're willing to go to $500 (save up money for a couple of extra months if need be), I'd recommend a Generation 4 Glock. Assuming you'll want to carry both open and concealed, I'd recommend either the model 26 (9mm) or the model 27 (.40 S&W). Here's some good things about them
1. The model 26 and 27 work easily for both open and concealed carry. Sometimes I carry my 27 openly in a hip holster; sometimes I conceal it and stick it in my front jeans pocket.
2. The model 26 and 27 can be adapted to act somewhat like the full-size versions. In other words, if you decide you want higher capacity magazines, keep in mind that they will accept the magazines from the larger model versions in the same caliber (the 26 will accept magazines designed for the 19 and 17; the 27 will accept magazines designed for the 23 and 22).
3. The Glock is very easy to disassemble and reassemble. For a basic field-strip, I can literally disassemble and reassemble my Glock in under a minute with my eyes shut (I've done it several times, occasionally with a blindfold).
4. The Generation 4 models give you some versatility. If you or your wife are left-handed, the magazine release button can be reversed to accomodate a left-handed shooter. Also, I noticed that you said you have medium to large sized hands. The Generation 4 Glocks come with two removable backstraps. The medium backstrap gives the same grip size as Gen 3 and earlier Glocks; no backstrap reduces the grip size by about 2mm (which was critical for me, since I have small hands); and the large backstrap adds 2mm to the grip size compared to Gen 3 and earlier Glocks. So, this might be important if you and your wife have significantly different hand sizes.
5. Glocks tend to be very reliable. Hence, if an extra $100 really is a dealbreaker, you can pick up a used one for around $400 and not have to worry about it.
Like the others, I really would not recommend .22 LR for defense. It's a good, cheap ammo to use for practice; and .22 ammo can be deadly. But, it won't bring the attacker down immediately and could give the attacker time to stab, shoot, or otherwise harm you before finally going down. In a defensive situation, you want to stop the threat as quickly as possible. To do so, you really need one of (what I call) the Big Three: 9mm, .40 S&W, or .45 ACP (there are Glocks available in .45 ACP; but they tend to be closer to $600). And, unless you live in New Jersey where they're illegal, please use hollowpoints. They'll stop the threat more quickly and reduce the risk of target over-penetration.